Medical Devices; Laboratory Developed Tests

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 809

[Docket No. FDA-2023-N-2177]

RIN 0910-AI85

Medical Devices; Laboratory Developed Tests

AGENCY:

Food and Drug Administration, HHS.

ACTION:

Final rule.

SUMMARY:

The Food and Drug Administration is issuing a final rule to amend its regulations to make explicit that in vitro diagnostic products (IVDs) are devices under the Federal Food, Drug, and Cosmetic Act (FD&C Act) including when the manufacturer of the IVD is a laboratory. In conjunction with this amendment, the Food and Drug Administration is phasing out its general enforcement discretion approach for laboratory developed tests (LDTs) so that IVDs manufactured by a laboratory will generally fall under the same enforcement approach as other IVDs. This phaseout policy includes enforcement discretion policies for specific categories of IVDs manufactured by a laboratory, including currently marketed IVDs offered as LDTs and LDTs for unmet needs. This phaseout policy is intended to better protect the public health by helping to assure the safety and effectiveness of IVDs offered as LDTs, while also accounting for other important public health considerations such as patient access and reliance.

DATES:

This rule is effective July 5, 2024.

ADDRESSES:

For access to the docket to read background documents or comments received, go to

https://www.regulations.gov

and insert the docket number found in brackets in the heading of this final rule into the “Search” box and follow the prompts, and/or go to the Dockets Management Staff, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852, 240-402-7500.

FOR FURTHER INFORMATION CONTACT:

Toby Lowe, Center for Devices and Radiological Health, Food and Drug Administration, 10903 New Hampshire Ave., Silver Spring, MD 20993, 301-796-6512,

LDTFinalRule@fda.hhs.gov.

SUPPLEMENTARY INFORMATION:

Table of Contents

I. Executive Summary

A. Purpose of the Final Rule

B. Summary of Select Provisions of the Final Rule

C. Legal Authority

D. Costs and Benefits

II. Table of Abbreviations/Commonly Used Acronyms in This Document

III. Background

A. FDA's Current Regulatory Framework

B. Need for the Rule

C. Summary of Comments on the Notice of Proposed Rulemaking

D. General Overview of the Final Amendment to the Definition of In Vitro Diagnostic Products

E. General Overview of the Final Phaseout Policy

IV. Legal Authority

V. Phaseout Policy

A. Scope

B. Enforcement Discretion Policies

C. Stages

VI. Comments on the Notice of Proposed Rulemaking and FDA Responses

A. General Comments on the Notice of Proposed Rulemaking

B. Definitions

C. Need for the Rule

D. FDA Authority To Regulate LDTs

E. Other Legal Comments

F. Phaseout Policy

G. Impact on Small Businesses

H. Impact on Pricing

I. Impact on Access and Innovation

J. Level Playing Field

K. Impact to Specific Patient Populations

L. Specific Types of IVDs

M. IVD Modifications

N. FDA Resources

O. 510(k) Third Party Review Program

P. Implementation

Q. Interplay With Oncology Drug Products Used With Certain In Vitro Diagnostic Tests Pilot Program

R. Miscellaneous

VII. Effective Date

VIII. Economic Analysis of Impacts

IX. Analysis of Environmental Impact

X. Paperwork Reduction Act of 1995

XI. Federalism

XII. Consultation and Coordination With Indian Tribal Governments

XIII. References

I. Executive Summary

A. Purpose of the Final Rule

The Food and Drug Administration (FDA, the Agency, or we) is amending its regulations to make explicit that IVDs are devices under the FD&C Act including when the manufacturer of the IVD is a laboratory. This amendment reflects that the device definition in the FD&C Act does not differentiate between entities manufacturing the device. In connection with amending the regulation, FDA is phasing out its general enforcement discretion approach for LDTs so that IVDs manufactured by a laboratory will generally fall under the same enforcement approach as other IVDs (

i.e.,

FDA's expectations for compliance will generally be the same). This phaseout policy includes enforcement discretion policies for specific categories of IVDs manufactured by a laboratory, including currently marketed IVDs offered as LDTs

1

and LDTs for unmet needs. For purposes of this document, we use “manufacture” and related terms as a shorthand for the various activities that constitute manufacturing as described in FDA regulations (

e.g.,

design, preparation, propagation, assembly, and processing).

1

As discussed in section V.A.1, FDA uses the phrase “IVDs offered as LDTs” throughout this preamble to refer to IVDs that are manufactured and offered as LDTs by laboratories that are certified under the Clinical Laboratory Improvement Amendments of 1988 (CLIA) and that meet the regulatory requirements under CLIA to perform high complexity testing, and used within such laboratories, even if those IVDs do not fall within FDA's traditional understanding of an LDT because they are not designed, manufactured, and used within a single laboratory.

In 1976, the Medical Device Amendments of 1976 (the MDA) amended the FD&C Act to create a comprehensive system for the regulation of devices intended for human use. In implementing the MDA, FDA has exercised enforcement discretion such that it generally has not enforced applicable requirements with respect to most LDTs. Enforcement discretion for LDTs developed as a matter of practice. However, the risks associated with LDTs are much greater today than they were at the time of enactment of the MDA. As discussed more fully in the notice of proposed rulemaking (NPRM) (88 FR 68006, October 3, 2023) and this preamble, today's LDTs are, among other things, used more widely, by a more diverse population, with an increasing reliance on high-tech instrumentation and software, and more frequently for the purpose of guiding critical healthcare decisions. In this regard, today's LDTs are similar to other IVDs that have not come within FDA's general enforcement discretion approach.

Given these changes, and for the additional reasons discussed in the NPRM and this preamble, FDA is phasing out the general enforcement discretion approach for LDTs. By phasing out this approach, FDA intends to better protect the public health by helping to assure the safety and effectiveness of IVDs offered as LDTs, while also accounting for other important public health considerations such as patient access and reliance.

B. Summary of Select Provisions of the Final Rule

FDA is amending the definition of “in vitro diagnostic products” in its regulations to state that IVDs are devices

under the FD&C Act “including when the manufacturer of these products is a laboratory.”

In conjunction with this amendment, FDA is phasing out the general enforcement discretion approach for LDTs. As discussed further in this preamble, however, FDA is adopting targeted enforcement discretion policies for several categories of IVDs manufactured by a laboratory in certain circumstances. As with any enforcement discretion policy, FDA may update any of these enforcement discretion policies as circumstances warrant or if the circumstances that inform these policies change, consistent with FDA's good guidance practices (21 U.S.C. 371(h), § 10.115 (21 CFR 10.115)).

Additional details regarding the phaseout policy are discussed further in section V of this preamble.

C. Legal Authority

FDA is issuing this rule under the Agency's general rulemaking authorities and statutory authorities relating to devices. These authorities include sections 201(h)(1), 301, 501, 502, 510, 513, 514, 515, 518, 519, 520, 701, 702, 704, and 801 of the FD&C Act (21 U.S.C. 321(h)(1), 331, 351, 352, 360, 360c, 360d, 360e, 360h, 360i, 360j, 371, 372, 374, and 381) and section 351 of the Public Health Service Act (PHS Act) (42 U.S.C. 262).

D. Costs and Benefits

We quantify benefits to patients from averted health losses due to problematic IVDs offered as LDTs. We focus mainly on certain broad disease categories associated with the majority of misdiagnosis-related harms in the United States. Additional benefits include averted non-health losses from reduced spending on problematic IVDs offered as LDTs and unquantified reduction in costs from lawsuits. We quantify costs to affected laboratories for complying with statutory and regulatory requirements. Additional costs include costs to FDA, which we include in our estimates. We estimate that the annualized benefits over 20 years range from $0.99 billion to $11.1 billion at a 7 percent discount rate, with a primary estimate of $3.51 billion, and from $1.24 billion to $13.62 billion at a 3 percent discount rate, with a primary estimate of $4.34 billion. The annualized costs range from $566 million to $3.56 billion at a 7 percent discount rate, with a primary estimate of $1.29 billion, and from $603 million to $3.79 billion at a 3 percent discount rate, with a primary estimate of $1.37 billion.

II. Table of Abbreviations/Commonly Used Acronyms in This Document

Abbreviation/acronym

What it means

3P510k Review Organization

Third Party Review Organization Accredited Under FDA's Third Party Review Program

510(k)

Premarket Notification.

AABB

Association for the Advancement of Blood and Biotherapies.

ACGME

Accreditation Council for Graduate Medical Education.

ACLA

American Clinical Laboratory Association.

ADLT

Advanced Diagnostic Laboratory Test.

ACHC

Accreditation Commission for Health Care.

AMC

Academic Medical Center.

AML

Acute Myeloid Leukemia.

AMP

Association for Molecular Pathology.

ANI

Average Nucleotide Identity.

APA

Administrative Procedure Act.

ASHI

American Society for Histocompatibility and Immunogenetics.

ASR

Analyte Specific Reagent.

AST

Antimicrobial Susceptibility Test.

BLA

Biologics License Application.

CAP

College of American Pathologists.

CAPA

Corrective and Preventive Action.

CBRN

Chemical, Biological, Radiological, or Nuclear.

CDER

Center for Drug Evaluation and Research.

CDRH

Center for Devices and Radiological Health.

CDC

Centers for Disease Control and Prevention.

CDx

Companion Diagnostic.

CFR

Code of Federal Regulations.

CGMP

Current Good Manufacturing Practice.

CGT

Cell and Gene Therapy.

CLIA

Clinical Laboratory Improvement Amendments of 1988.

CLIAC

Clinical Laboratory Improvement Advisory Committee.

CLSI

Clinical and Laboratory Standards Institute.

CMS

Centers for Medicare & Medicaid Services.

COLA

Commission on Office Laboratory Accreditation.

CRO

Clinical Research Organization.

Cures Act

21st Century Cures Act.

DNA

Deoxyribonucleic Acid.

DoD

Department of Defense.

EGFR

Epidermal Growth Factor Receptor.

EMR

Electronic Medical Record.

EO

Executive Order.

EUA

Emergency Use Authorization.

EUCAST

European Committee on Antimicrobial Susceptibility Testing.

FACT

Foundation for the Accreditation of Cellular Therapy.

FCC

Federal Communications Commission.

FDA

Food and Drug Administration.

FDAAA

Food and Drug Administration Amendments Act.

FDAMA

Food and Drug Administration Modernization Act.

FDA-ARGOS

FDA dAtabase for Reference Grade MicrObial Sequences.

FD&C Act

Federal Food, Drug, and Cosmetic Act.

FRIA

Final Regulatory Impact Analysis.

GAO

Government Accountability Office.

HCFA

Health Care Financing Administration.

HCT/Ps

Human Cells, Tissues, and Cellular and Tissue-Based Products.

HDE

Humanitarian Device Exemption.

HHS

Department of Health & Human Services.

HIV

Human Immunodeficiency Virus.

HLA

Human Leukocyte Antigen.

HUD

Humanitarian Use Device.

ICCS

International Clinical Cytometry Society.

IDE

Investigational Device Exemption.

IND

Investigational New Drug Application.

ISO

International Organization for Standardization.

IVD

In Vitro Diagnostic Product.

IVDR

In Vitro Diagnostic Medical Device Regulation.

LDT

Laboratory Developed Test.

LGBTQIA+

Lesbian, Gay, Bisexual, Transgender, Queer, Intersex, and Asexual.

LoQ

Limit of Quantitation.

MAF

Master File.

MDA

Medical Device Amendments of 1976.

MDAC

Medical Devices Advisory Committee.

MDR

Medical Device Report.

MDUFA

Medical Device User Fee Amendments.

MolDx

Molecular Diagnostic Services.

NCBI

National Center for Biotechnology Information.

NDA

New Drug Application.

NGS

Next Generation Sequencing.

NIFLA

National Institute of Family and Life Advocates.

NIH

National Institutes of Health.

NIPS

Non-Invasive Prenatal Screening.

NLRB

National Labor Relations Board.

NMDP

National Marrow Donor Program.

NOTA

National Organ Transplant Act.

NPRM

Notice of Proposed Rulemaking.

NSQAP

Newborn Screening Laboratory Quality Assurance Program.

NYS CLEP

New York State Department of Health's Clinical Laboratory Evaluation Program.

OED

Oxford English Dictionary.

OHT7

Office of Health Technology 7.

OIRA

Office of Information and Regulatory Affairs.

OMB

Office of Management and Budget.

OPTN

Organ Procurement and Transplant Network.

OTC

Over-the-Counter.

PAMA

Protecting Access to Medicare Act of 2014.

PCCP

Predetermined Change Control Plan.

PHS Act

Public Health Service Act.

PMA

Premarket Approval Application.

PrEP

Pre-Exposure Prophylaxis.

PRIA

Preliminary Regulatory Impact Analysis.

QS

Quality System.

QSR

Quality System Regulation.

RBC

Red Blood Cell.

RNA

Ribonucleic Acid.

RUO

Research Use Only.

SAMHSA

Substance Abuse and Mental Health Services Administration.

SDO

Standards Development Organization.

Secretary

Secretary of HHS.

STI

Sexually Transmitted Infection.

STIC

Susceptibility Test Interpretive Criteria.

TMB

Tumor Mutational Burden.

UDI

Unique Device Identification.

UMRA

Unfunded Mandates Reform Act of 1995.

USG

United States Government.

VALID Act

Verifying Accurate, Leading-Edge IVCT Development Act of 2023.

VHA

Veterans Health Administration.

III. Background

FDA's regulations define IVDs as reagents, instruments, and systems intended for use in the diagnosis of disease or other conditions, including a determination of the state of health, in order to cure, mitigate, treat, or prevent disease or its sequelae, and intended for use in the collection, preparation, and examination of specimens taken from the human body. IVDs include test systems (also referred to in this preamble as “tests”) that are intended for use in the collection, preparation, and examination of samples taken from the human body, such as blood or tissue, for the purpose of detecting diseases or other conditions, monitoring

a person's overall health, identifying patients who are likely to benefit from specific therapies, or otherwise helping to diagnose, cure, mitigate, treat, or prevent disease or its sequelae. Some IVDs are manufactured by conventional medical device manufacturers for use by other entities such as laboratories, healthcare providers, or, in some cases, patients. Such IVDs may include “test kits,” containing packaged sets of components that are part of or comprise a test system. Other IVDs are manufactured by laboratories for use by the same or other laboratories. Such IVDs include LDTs. FDA has generally considered an LDT to be an IVD that is intended for clinical use and that is designed, manufactured, and used within a single laboratory that is certified under the Clinical Laboratory Improvement Amendments of 1988 (CLIA) and meets the regulatory requirements under CLIA to perform high complexity testing.

2

2

Such laboratories may include those operating under State licensure programs deemed exempt from CLIA.

See

CMS, “Exempt States Under the Clinical Laboratory Improvement Amendments” (Ref. 1).

However, in implementing the MDA since 1976, FDA has exercised enforcement discretion such that it generally has not enforced applicable legal requirements with respect to most LDTs. This means that, for most LDTs, FDA generally has not enforced requirements related to registration and listing, reporting adverse events to FDA, current good manufacturing practices (CGMPs), or premarket review of an IVD by FDA prior to use of the LDT in patient care, among other requirements. The rationale for this approach was that, at the time of passage of the MDA, LDTs were mostly manufactured in small volumes by laboratories that served their local communities. They were typically intended for use in diagnosing rare diseases or for other uses to meet the needs of a local patient population, or were generally similar to well-characterized, standard IVDs (Refs. 2 and 3). They also tended to employ manual techniques (and did not use automation) and were performed by laboratory personnel with specialized expertise; to be used and interpreted by physicians or pathologists in a single institution responsible for the patient (and who were actively involved in patient care); and to be manufactured using components legally marketed for clinical use, such as general purpose reagents or immunohistochemical stains marketed in compliance with FDA requirements. Due to these and other factors, FDA exercised enforcement discretion such that it generally has not enforced applicable requirements for most LDTs.

3

3

FDA's general enforcement discretion approach has not applied to LDTs in all contexts; for example, it has not applied to, among other LDTs, those used for declared emergencies/potential emergencies/material threats under section 564 of the FD&C Act (21 U.S.C. 360bbb-3).

However, the LDT landscape has evolved significantly since 1976. Today, many LDTs increasingly rely on high-tech or complex instrumentation and software to generate results and clinical interpretations (Refs. 2 and 3). They are often used in laboratories outside of the patient's healthcare setting and are often run in high volume for large and diverse populations. Many LDTs are manufactured by laboratory corporations that market the IVDs nationwide, as they accept specimens from patients across the country and run their LDTs in very large volumes in a single laboratory. Today's LDTs are also more commonly manufactured with instruments or other components not legally marketed for clinical use and are more often used to inform or direct critical treatment decisions, to widely screen for common diseases, to predict personal risk of developing certain diseases, and to diagnose serious medical conditions such as cancer and heart disease.

4

The risks associated with most LDTs today are therefore much greater than they were at the time FDA began implementing the MDA, and most LDTs today are similar to other IVDs that have not been under FDA's general enforcement discretion approach. In addition, FDA is concerned that firms are offering IVDs as “LDTs” even when they are not LDTs as defined on FDA's website, because they are not actually designed, manufactured, and used within a single laboratory (see,

e.g.,

Refs. 5 and 6).

4

See, e.g.,

Refs. 2-4. These observations are also informed by FDA's own experience, including the review of submissions and site visits, and staff with prior experience in the laboratory industry manufacturing and performing LDTs.

As LDTs increasingly rely on high-tech instrumentation and software, the potential for cybersecurity vulnerabilities is growing. Many LDTs are connected to Laboratory Information Management Systems and other IT infrastructure, making them a potential conduit for those looking to access information in such systems. This may include patient genetic information, among other things, which could have national security implications. Further, it has been demonstrated that hackers can modify medical test results (Ref. 7). Through premarket review, FDA works with manufacturers to ensure cybersecurity is appropriately considered, mitigating the potential for future problems. Through medical device reporting (MDR) and correction and removal reporting requirements, FDA helps to ensure that any problems are appropriately addressed. In fact, FDA has seen cybersecurity problems with certain instruments and issued two safety communications where laboratories may not have otherwise been aware that the research use only (RUO) versions of the instruments used as part of their LDTs had the same vulnerabilities (Refs. 8 and 9).

As a result of these evolutions in the testing landscape, FDA has long recognized the need for a change in the Agency's general enforcement discretion approach for LDTs. The history of FDA's efforts with respect to LDTs is described more fully in the NPRM. Over the past few years, FDA has accumulated even more information supporting the need for a change, as noted in the NPRM and discussed below. In light of these developments, FDA is amending FDA's regulations to make explicit that IVDs are devices under the FD&C Act including when the manufacturer is a laboratory.

5

FDA is also issuing a policy (see section V) under which FDA is: (1) phasing out its general enforcement discretion approach for LDTs so that IVDs manufactured by a laboratory will generally fall under the same enforcement approach as other IVDs and (2) adopting targeted enforcement discretion policies for specific categories of IVDs manufactured by a laboratory. As reflected in FDA's Final Regulatory Impact Analysis (FRIA), FDA estimates that the benefits of the phaseout policy outweigh the costs (see Ref. 10).

5

FDA is also amending the statutory citation for the device definition included in § 809.3 (21 CFR 809.3) to reflect that it is now codified at section 201(h)(1) of the FD&C Act.

A. FDA's Current Regulatory Framework

A comprehensive system for the regulation of devices is included in the FD&C Act, as amended by the MDA. Section 513 of the FD&C Act (21 U.S.C. 360c) establishes three categories (classes) of devices depending on the regulatory controls needed to provide reasonable assurance of their safety and effectiveness. The three categories of devices are class I (general controls), class II (special controls), and class III (premarket approval).

Class I devices are those devices for which the general controls of the FD&C Act (controls authorized by or under section 501, 502, 510, 516, 518, 519, or 520 (21 U.S.C. 351, 352, 360, 360f, 360h, 360i, or 360j) or any combination of

such sections) are sufficient to provide reasonable assurance of safety and effectiveness of the device; or those devices for which insufficient information exists to determine that general controls are sufficient to provide reasonable assurance of safety and effectiveness or to establish special controls to provide such assurance, but because the devices are not purported or represented to be for a use in supporting or sustaining human life or for a use which is of substantial importance in preventing impairment of human health, and do not present a potential unreasonable risk of illness or injury, are to be regulated by general controls (section 513(a)(1)(A) of the FD&C Act).

General controls include, but are not limited to, provisions that relate to establishment registration and device listing; premarket notification; prohibitions against adulteration and misbranding (

e.g.,

labeling that fails to bear adequate directions for use); recordkeeping and reporting, including adverse event reporting and reporting of corrections and removals initiated to reduce a risk to health posed by the device or to remedy a violation of the FD&C Act caused by the device which may present a risk to health; investigational device exemption (IDE) requirements;

6

and CGMP requirements. These controls apply to all devices unless an exemption applies.

6

Under section 520(g) of the FD&C Act and part 812 of FDA's regulations (21 CFR part 812), a clinical investigation to determine the safety and effectiveness of certain devices must be the subject of an approved IDE before such investigation may commence. If an IDE has been granted, a failure to comply with a requirement under which the device was exempted for investigational use renders the device adulterated (see section 501(i) of the FD&C Act).

Class II devices are those devices for which general controls by themselves are insufficient to provide reasonable assurance of safety and effectiveness, but for which there is sufficient information to establish special controls to provide such assurance, including the promulgation of performance standards, post-market surveillance, patient registries, development and dissemination of guidelines, recommendations, and other appropriate actions the Agency deems necessary to provide such assurance (section 513(a)(1)(B) of the FD&C Act).

Class III devices are those devices for which insufficient information exists to determine that general controls and special controls would provide a reasonable assurance of safety and effectiveness, and are purported or represented for a use in supporting or sustaining human life or for a use which is of substantial importance in preventing impairment of human health, or present a potential unreasonable risk of illness or injury (section 513(a)(1)(C) of the FD&C Act).

Under section 513(d)(1) of the FD&C Act, devices that were introduced or delivered for introduction into interstate commerce for commercial distribution before the enactment of the MDA on May 28, 1976 (generally referred to as “preamendments devices”) are classified after FDA: (1) receives a recommendation from a device classification panel (an FDA advisory committee); (2) publishes the panel's recommendation, along with a proposed regulation classifying the device, and provides an opportunity for interested persons to submit comments; and (3) publishes a final regulation classifying the device. A preamendments device for which a classification regulation has not been promulgated is known as an “unclassified device.” Until an unclassified device type has been formally classified by regulation, the marketing of new devices within the device type requires FDA premarket review through a premarket notification (510(k)) under section 510(k) of the FD&C Act.

Devices that were not introduced or delivered for introduction into interstate commerce for commercial distribution before May 28, 1976 (generally referred to as “postamendments devices”) are classified automatically by section 513(f) of the FD&C Act into class III without any FDA rulemaking process. Those devices remain in class III and require approval of a premarket approval application (PMA), unless and until: (1) FDA classifies or reclassifies the device into class I or II under section 513(f)(2) or (3) of the FD&C Act, or (2) FDA issues an order finding the device to be substantially equivalent, in accordance with section 513(i) of the FD&C Act, to a predicate device that does not require premarket approval. The Agency determines whether new devices are substantially equivalent to predicate devices by means of premarket notification procedures in section 510(k) of the FD&C Act and part 807 of the regulations (21 CFR part 807).

Failure to comply with applicable requirements of the FD&C Act and FDA regulations may render the device adulterated and misbranded under sections 501 and 502 of the FD&C Act and may constitute a prohibited act under section 301 of the FD&C Act (21 U.S.C. 331). For a further discussion of these regulatory measures, and specifically how they help to ensure device safety and effectiveness, see section III.B.1 of this preamble.

IVDs, as defined in § 809.3 (21 CFR 809.3), are devices intended for human use and are subject to the FD&C Act. They include class I, class II, and class III devices, as well as both preamendments and postamendments devices. Like other devices, IVDs are subject to general controls, and other applicable requirements under the FD&C Act and FDA's regulations. IVDs are also subject to specific labeling requirements in part 809 of the regulations (21 CFR part 809).

For additional discussion of how FDA's legal authorities apply to LDTs, see the “Legal Basis for the Amendment” section (section V.B) of the NPRM (88 FR 68006 at 68017) and sections VI.D and VI.E of this preamble.

B. Need for the Rule

This final rule is the culmination of years of study and deliberation by FDA and represents a significant step forward for public health. By phasing out the general enforcement discretion approach for LDTs, FDA is correcting the imbalance in its oversight between non-laboratory and laboratory IVD manufacturers—an imbalance that harms American patients. As a result of the final phaseout policy, the public will benefit from laboratory manufacturer compliance with basic FDA requirements that protect and promote public health, such as adverse event reporting, establishment registration and device listing, labeling standards, investigational use requirements and, as new IVDs enter the market or are significantly modified, CGMPs and premarket review. Compliance with these time-tested regulatory measures will put patients in a better position to understand and have confidence in IVDs regardless of where they are manufactured. FDA believes that the benefits of this rulemaking will become more and more pronounced over time, as new IVDs come on the market and as the circumstances in which we exercise enforcement discretion narrow correspondingly (as discussed in section V.B of this preamble).

FDA has considered a wide array of input on this topic. In light of that input, we have adapted our thinking and adjusted the phaseout policy in a manner that we believe best serves the public health. The final phaseout policy, as set forth in section V of this preamble, fulfills the core goal of greater oversight of laboratory-manufactured IVDs while also accounting for other key public health interests, such as helping to maintain access to those beneficial IVDs on which patients currently rely and access to certain IVDs for which

there is little financial incentive for development. This final phaseout policy reflects a careful balancing of relevant factors and, overall, will substantially promote and protect public health, both now and in the future.

1. The Device Regulatory Scheme Advances Public Health, Including as Applied to Laboratory Manufacturers

Since Congress first enacted the FD&C Act, over time and across a wide range of product areas, Congress has empowered FDA with a standard set of tools to manage the risks (and, as applicable, help assure the effectiveness) of regulated products.

See

21 U.S.C. 393(b). These tools—such as adverse-event reporting, establishment registration and product listing, labeling standards, investigational controls, CGMPs, and premarket review—routinely appear in FDA statutory schemes because they effectively serve the public. See section IV for a more complete description of these authorities. As applied to devices, these regulatory measures help ensure product safety and effectiveness and facilitate greater information production and sharing, among other things.

7

FDA anticipates that compliance with these regulatory measures will have equal benefit in the context of laboratory-manufactured IVDs.

8

7

See, e.g.,

Ref. 11 (finding, for stents, that the testing required under U.S. device premarket review standards improves consumer welfare and reflects “optimal policy in terms of trading off testing versus access to innovation”—while also noting that post-market surveillance or learning could theoretically yield the same benefits as pre-market review at lower cost); Ref. 12 (noting that one benefit of “approval regulation” is the collection of “information useful to `downstream' product users,” such as physicians, who then “exhibit higher consumption and will more readily switch to superior products”); Ref. 13 (“The FDA is a critical component to the industries' success because it (1) provides appropriate reviews for safety and effectiveness, and (2) helps provide consumers with confidence that these technologies are safe and effective.”).

8

See, e.g.,

Ref. 14 (“Negative consequences of poorly understood or weakly applied regulatory oversight processes for laboratory developed tests have been vividly demonstrated . . . . Failure to insist on good clinical and laboratory practices, apply rigorous standards for the design, conduct, and analysis of biomedical research, and implement safeguards to address conflicts of interest poses threats to the integrity of biomedical research and exposes patients to potential harms.”); Ref. 15 (“Increasing regulatory responsibilities and requirements could encourage laboratories seeking to introduce LDTs . . . to prioritize tests with the greatest potential to positively affect patient care, which could reduce the clutter of available assays with limited utility.”).

For example, FDA expects that laboratory compliance with MDR requirements will yield significant public health benefits. Today, clinical laboratories comply with CLIA, which means that complaints are investigated and monitored generally only on a laboratory-by-laboratory basis. That approach makes sense in light of CLIA's focus on individual laboratory operations. However, FDA is focused on identifying problems with an IVD itself—such as design or other manufacturing problems—so FDA looks for different types of errors and applies a different analysis to the MDRs it receives. Among other things, FDA aggregates MDR information across IVD types for tracking and trending, enabling the detection of issues that a single laboratory may never see. FDA has identified and helped resolve a wide range of IVD issues using this type of information (see the response to comment 165 for additional information). For example, using MDRs submitted by multiple manufacturers, FDA discovered that high dose biotin supplements were interfering with certain immunoassays (biotin is commonly used in the design of these assays), which caused inaccurate results among those tests. FDA's investigation of the issue—an issue that could apply equally to laboratory-manufactured tests—led to the redesign of multiple tests on the market (see also comment response 122). In order to maximize the value of medical device reporting, FDA's Office of Health Technology 7 (OHT7): Office of In Vitro Diagnostics, within the Office of Product Evaluation and Quality in FDA's Center for Devices and Radiological Health (CDRH), employs trained staff dedicated to the review of MDRs for each IVD product code. These efforts help ensure that FDA catches and addresses potentially problematic IVDs to better protect the public.

Compliance with registration and listing requirements will also have substantial public health value. The collection of this information provides FDA with the location of device establishments and all devices manufactured at those establishments. Knowledge of the location where devices are manufactured allows for effective planning, coordinating, and scheduling of inspections, ensuring that FDA has visibility into the operations and practices at different manufacturing facilities. Through inspections, FDA has been able to determine when manufacturers have deficient processes, such as failure to investigate complaints and adverse events (which can signal larger problems, as just described). Although CLIA inspections occur for laboratories, such inspections do not have the same focus on design issues, for example, such as design changes that fundamentally alter the IVD's safety or effectiveness and present novel risks to patients. In addition, compliance with listing requirements will give FDA better information about the universe of IVDs on the market. With respect to the biotin interference issue discussed earlier, for example, FDA's investigation led to the redesign of affected tests in FDA's listing database, but FDA did not have insight into laboratory developed tests on the market that might have the same issue because they were not in the database. It is possible that laboratories today are

still

manufacturing and offering tests with inaccurate results due to biotin interference. With greater listing information, FDA can better protect the public through more comprehensive remediation efforts, among other things. FDA's publicly accessible registration and listing database also gives the public greater knowledge of IVD manufacturers and the range of IVDs on the market, which will benefit patients and providers who seek to better understand the different testing options that are available and the source and location of those testing options. Right now, as noted in the FRIA, there is no reliable inventory of IVDs on the market. More comprehensive information will do a great service to the public and improve patient care.

Laboratory compliance with FDA labeling requirements will also materially advance public health, because it will provide for the availability of a consistent set of information critical to understanding the IVD, whether the IVD is manufactured by a laboratory or another manufacturer. The labeling requirements in § 809.10 (21 CFR 809.10) require IVD manufacturers to disclose basic facts about an IVD that can inform a doctor or patient's selection decisions, such as the intended use, limitations, and performance characteristics of the test. Today, ordering physicians do not necessarily have access to this standardized set of information for IVDs offered as LDTs, and therefore may lack the information needed to understand the use and performance of tests for their intended uses, make decisions in the context of an individual patient's needs, and pass on relevant information to their patients. Laboratory compliance with labeling requirements will mean that laboratories both compile and provide access to this type of information, which will facilitate knowledge transfer and, consequently, more informed healthcare decisions. Labeling also provides a frame of

reference for evaluating a manufacturer's promotional claims, helping FDA determine, for example, whether manufacturers may be misleading the public about the safety or effectiveness of their IVDs. Based on the various lawsuits cited in the NPRM (88 FR 68006 at 68012), FDA is aware that such promotion may be taking place and should be addressed.

FDA is also aware that, today, laboratories are conducting IVD clinical investigations without complying with FDA requirements, including the requirement to submit an IDE application for FDA review before beginning studies involving “significant risk” IVDs. When this occurs, subjects may be enrolled in studies that lack key human subject protections. Among other things, such investigations may lack an appropriate evaluation of whether, for example, the informed consent documents that are provided to potential subjects contain adequate information about the reasonably foreseeable risks or potential benefits of participation in the study. Such investigations of significant risk IVDs may also lack review by FDA to evaluate whether there are sufficient data to justify use of a significant risk IVD in the proposed study population. As explained in an FDA memorandum to file that was part of the record for this rulemaking, FDA is aware of circumstances in which laboratories have failed to conduct appropriate analytical validation studies to support the use of tests in clinical investigations (Ref. 16). In these instances, in the absence of FDA review of these investigations, subjects may have been enrolled in studies that exposed them to safety risks with little potential for benefit or for generating useful information.

Laboratory compliance with CGMP requirements will benefit the public as well. The Quality System Regulation (QSR) requires manufacturers to establish procedures for the consistent, quality manufacturing of devices. FDA recently issued comprehensive amendments to harmonize the QSR with international quality management system requirements (89 FR 7496, February 2, 2024). Under FDA's quality system (QS) requirements, design controls are a key area of focus, and an area that is distinct from CLIA (see the response to comment 188 for further information). Design controls require manufacturers to have procedures for generating IVD specifications, making sure their IVDs actually meet those specifications, and confirming that those specifications conform with user needs and intended use(s). By establishing and following a set system of documentation, manufacturers approach device design and modifications systemically, ensuring that the original design and any changes have been properly evaluated and do not have unintended consequences. In 1990, Congress specifically granted FDA authority to issue design control requirements after the Agency found that 44 percent of the quality problems that had led to voluntary recall actions between 1983 and 1989 were due to design errors or deficiencies, and the Agency promulgated corresponding QS regulations in 1996 (61 FR 52602, October 7, 1996). Design controls play such a key role because, as FDA explained when it issued those regulations, “[t]he intrinsic quality of devices, including their safety and effectiveness, is established during the design phase” (61 FR 52602 at 52615). Other QS requirements help ensure effective and appropriate design, such as acceptance activities, corrective and preventive actions, and records requirements. Although FDA recognizes that compliance with the QS requirements is associated with relatively higher costs for laboratories, and has taken that fact into account in crafting the phaseout policy, FDA believes laboratory compliance with the requirements generally will advance public health.

Finally, premarket review is one of FDA's most important tools for protecting and promoting public health. Through premarket review, the Agency evaluates the scientific information supporting the analytical validity, clinical validity, and safety of high- and moderate-risk IVDs, which helps ensure the IVD's safety and effectiveness before it reaches a patient. In FDA's experience, premarket review serves an important gatekeeping function regardless of whether an IVD is manufactured by a laboratory or another manufacturer. For example, FDA has received submissions for IVDs offered as LDTs showing that laboratories do not always properly validate tests or have sound clinical data to support a test's intended use (Ref. 16). If marketed as originally presented to FDA, many of these tests could have led to missed diagnoses or misdiagnoses, improper patient management decisions, or missed opportunities for beneficial treatment. Through premarket review, FDA works with applicants to obtain adequate data, determine whether a device works as intended, and refine labeling to reflect the intended use and limitations of an IVD. This process motivates the development of robust scientific data on safety and effectiveness

9

and gives patients confidence that an independent, expert third party has determined that patients can rely on these IVDs. FDA has recognized circumstances in the final phaseout policy in which the benefits of laboratory compliance with premarket review requirements are outweighed by other public-health considerations. The Agency will exercise enforcement discretion in those circumstances, as described below. Apart from these circumstances, FDA expects that laboratory compliance with premarket review requirements will have a significant positive impact on public health.

9

See Ref. 17.

2. The Oversight Approach Set Forth in This Preamble Will Advance Public Health

Those who object to this rulemaking appear to argue that the IVDs manufactured by laboratories are so fundamentally different from, or better than, other IVDs that these IVDs should not fall under the oversight scheme outlined above. But these commenters are not able to point to differences that logically sustain that position. Many laboratory-manufactured tests use the same materials and technology, are based on the same scientific principles, are intended for the same or similar purposes, are developed by those with similar expertise, require the same level of training to perform, and are marketed for the same patients as tests from other manufacturers. Although some activities of these laboratories are also subject to CLIA, CLIA is not a substitute for FDA oversight, as detailed throughout this preamble and as the Centers for Medicare & Medicaid Services (CMS) has explained.

Furthermore, a review of the evidence does not bear out the suggestion that laboratory-manufactured IVDs have higher quality or perform better than other IVDs. FDA's memorandum to file describing submissions for IVDs offered as LDTs detailed the many defects FDA has seen with laboratory validation, among other things, and described the submissions as raising “significant concerns” in some cases (Ref. 16). During the COVID-19 emergency, FDA's conversations with laboratory manufacturers revealed that many were unfamiliar with what constitutes appropriate analytical and clinical validation for an IVD generally (see comment response 37 and Ref. 18). FDA's experience is corroborated by new information in the record from New York State. New York State submitted

data indicating that more than half of original applications from laboratories could not be approved by the New York State Department of Health Clinical Laboratory Evaluation Program (NYS CLEP) based on deficiencies such as “design flaws, inadequate validation data, and process problems that call into question the reliability of the results” (Ref. 19). And in one of the only true head-to-head comparisons between IVDs offered as LDTs and the parallel FDA-authorized IVD,

10

the IVDs offered as LDTs were less accurate than the FDA-authorized IVD (Ref. 20). Although some commenters suggested that a reanalysis of that data supports a different conclusion, even under the reanalysis, the laboratory tests had worse performance, with only 8 of 19 laboratories correctly reporting all variants (compared to 7 in the original analysis). For additional information about the analysis and reanalysis, see comment responses 34 and 38.

11

10

For purposes of this preamble, “FDA-authorized” refers to FDA permitting the marketing of a device via the premarket approval, 510(k), De Novo classification, Biologics License Application (BLA), or Humanitarian Device Exemption (HDE) pathway and to devices that are exempt from premarket notification. This term does not include devices authorized for emergency use under section 564 of the FD&C Act.

11

For additional discussion of evidence relevant to IVDs offered as LDTs, see section III.B.2 of the NPRM (88 FR 68006 at 68010-12).

In short, based on the information before us, we do not believe that the general enforcement discretion approach for LDTs should continue. Today, IVDs offered as LDTs do not have appropriate assurances of safety and effectiveness. At least one survey suggests that the public agrees.

12

Therefore, FDA is phasing out the general enforcement discretion approach for LDTs, as explained in more detail in section V.

12

Ref. 21 (“When presented with information on the differences between FDA regulation and CMS oversight, most participants supported FDA having oversight over all diagnostic tests.”).

However, FDA also recognizes the effect that its longstanding enforcement discretion approach has had on the market, the role that laboratory-manufactured tests play in modern healthcare, and the presence of other expert regulatory bodies. Many comments emphasized these considerations. FDA agrees with certain comments' concern, for example, that expecting compliance with full QS and premarket review requirements for all currently marketed IVDs offered as LDTs could lead to the loss of access to safe and effective IVDs on which patients currently rely, and we are issuing an enforcement discretion policy to address that issue (see section V.B.3). FDA also agrees with the concern that, for certain LDTs for unmet needs, expecting full compliance with FDA requirements could lead to loss of access to tests for unmet needs for which laboratories cannot recoup the costs of compliance; we are issuing an enforcement discretion policy to address that issue in circumstances in which certain risk mitigations apply (see section V.B.3). FDA has also incorporated enforcement discretion policies recognizing the regulatory role that other Federal and State entities play (see sections V.B.1 and 2). In these and other ways, FDA has crafted a tailored phaseout policy that balances the important public health considerations at issue in this rule.

We anticipate that the final phaseout policy will provide significant benefits to the public. As indicated in the FRIA, the anticipated benefits significantly outweigh the anticipated costs. Through this Agency action, patients will have greater assurance that the IVDs used in their care are safe and effective, a significant step forward for public health. In addition, by applying the same general oversight approach to laboratories and non-laboratories that manufacture IVDs, FDA will reduce regulatory uncertainty, which will give stakeholders more stability, clarity, and confidence, and facilitate investment in the development of innovative IVDs (Ref. 22). FDA oversight will help to support coverage and reimbursement determinations for IVDs offered as LDTs, which we anticipate will make certain IVDs offered as LDTs for which there is a reasonable assurance of safety and effectiveness more affordable for patients. And with increased oversight, FDA will be able to help promote adequate representation in validation studies, and transparency regarding potential differential performance and unknown performance in certain patient populations, which will ultimately help advance health equity (see comment response 221 for additional information).

FDA expects the benefits of the phaseout policy to become more and more pronounced over time, as new tests come on the market and as the circumstances in which we exercise enforcement discretion narrow correspondingly. Diagnostic testing is increasingly important; for example, as time goes on, more novel treatments will require use of a specialized test to identify patients likely to benefit from those treatments.

13

Furthermore, IVDs offered as LDTs are a growing sector of the diagnostic testing market (Ref. 4). FDA anticipates that IVDs will continue to become more complex and play a greater role in modern healthcare (Ref. 3). The U.S. LDT market size is anticipated to grow 6 percent from 2023 to 2030 due to varying factors including increased use in personalized medicine and rising prevalence of chronic diseases. (

Id.

) FDA is therefore taking steps to help ensure that IVDs are safe and effective regardless of where they are manufactured, so that both now and in the future, patients can have confidence about the tests used in their care.

13

See, e.g.,

Ref. 23 (“Demand is increasing in the CDx market, due to the paradigm shift to precision medicine.”).

C. Summary of Comments on the Notice of Proposed Rulemaking

In the

Federal Register

of October 3, 2023, FDA published a rule proposing an amendment to its regulations to make explicit that IVDs are devices under the FD&C Act including when the manufacturer is a laboratory, and proposing a policy under which FDA would phase out its general enforcement discretion approach for LDTs. The comment period for the NPRM closed on December 4, 2023. FDA received more than 6,500 comments on the NPRM from a variety of entities including medical device associations, members of the medical device and pharmaceutical industries, medical and healthcare professional associations, hospitals and academic medical centers (AMCs), accreditation organizations, other advocacy organizations, government agencies, and individuals.

Comments supporting FDA's proposal pointed to problems with LDTs, concerns about the significant impact of problematic LDTs on patients and the treatment decisions of healthcare providers, and the need for increased oversight of LDTs by FDA. Some comments also emphasized the importance of creating a “level playing field” between laboratory and non-laboratory manufacturers of IVDs, and described how phasing out the general enforcement discretion approach for LDTs would incentivize innovation by non-laboratory IVD manufacturers.

Some comments raised concerns or requested clarification regarding the following:

• the evidence related to the safety or effectiveness of IVDs offered as LDTs,

• the sufficiency of regulation by CMS and other non-FDA entities,

• FDA's legal authority to regulate LDTs,

• the impact of the phaseout policy on access to and the pricing of IVDs offered as LDTs,

• the impact of the phaseout policy on test innovation,

• the impact of the phaseout policy on small laboratories,

• the impact of the phaseout policy on specific patient populations, including underrepresented and underserved populations,

• the details of the phaseout policy,

• the types of IVDs offered as LDTs for which FDA intends to continue the general enforcement discretion approach and generally not enforce some or all applicable requirements, and

• FDA's implementation of the phaseout policy and the resources needed for such implementation.

D. General Overview of the Final Amendment to the Definition of In Vitro Diagnostic Products

FDA is amending its regulations to make explicit that IVDs are devices under the FD&C Act including when the manufacturer of the IVD is a laboratory. This amendment reflects that the device definition in the FD&C Act does not differentiate between entities manufacturing the device, and provides further clarity, including for stakeholders affected by the accompanying changes to FDA's general enforcement discretion approach for LDTs.

FDA is also amending the statutory citation for the device definition included in § 809.3 to reflect amendments to section 201(h) of the FD&C Act as a result of the enactment of the Safeguarding Therapeutics Act (Pub. L. 116-304). For many years, the definition of “device” had been codified at section 201(h) of the FD&C Act. Upon enactment of the Safeguarding Therapeutics Act, the definition of “device” was redesignated as paragraph (h)(1) and a new definition of “counterfeit device” was codified at paragraph (h)(2).

FDA considered comments received on the NPRM, as discussed in more detail throughout this preamble, and has made no changes to the amendment.

E. General Overview of the Final Phaseout Policy

FDA has had a general enforcement discretion approach for most LDTs.

14

FDA is phasing out this general enforcement discretion approach so that IVDs manufactured by a laboratory will generally fall under the same enforcement approach as other IVDs. The phaseout is intended to help assure the safety and effectiveness of IVDs offered as LDTs, while also accounting for other important public health considerations such as patient access and reliance.

14

As discussed further in section V.A.2, FDA's general enforcement discretion approach has not applied to certain categories of LDTs. For these categories of LDTs, FDA has generally expected applicable requirements to be met, and in the NPRM we proposed that this approach be maintained (88 FR 68006 at 68021). After considering comments received on this topic we are not changing that approach for these categories with the phaseout policy described in this preamble.

Following a 4-year phaseout period, FDA will no longer have a general enforcement discretion approach for LDTs. The phaseout policy includes the following five stages for IVDs offered as LDTs (a term discussed further in section V.A.1):

•

Stage 1:

beginning 1 year after the publication date of this final rule, FDA will expect compliance with MDR requirements, correction and removal reporting requirements, and QS requirements under § 820.198 (21 CFR 820.198) (complaint files);

•

Stage 2:

beginning 2 years after the publication date of this final rule, FDA will expect compliance with requirements not covered during other stages of the phaseout policy, including registration and listing requirements, labeling requirements, and investigational use requirements;

•

Stage 3:

beginning 3 years after the publication date of this final rule, FDA will expect compliance with QS requirements under part 820 (21 CFR part 820) (other than requirements under § 820.198 (complaint files), which are already addressed in stage 1);

•

Stage 4:

beginning 3

1/2

years after the publication date of this final rule, FDA will expect compliance with premarket review requirements for high-risk IVDs offered as LDTs (IVDs that may be classified into class III or that are subject to licensure under section 351 of the Public Health Service Act), unless a premarket submission has been received by the beginning of this stage in which case FDA intends to continue to exercise enforcement discretion for the pendency of its review; and

•

Stage 5:

beginning 4 years after the publication date of this final rule, FDA will expect compliance with premarket review requirements for moderate-risk and low-risk IVDs offered as LDTs (that require premarket submissions), unless a premarket submission has been received by the beginning of this stage in which case FDA intends to continue to exercise enforcement discretion for the pendency of its review.

The phaseout policy includes targeted enforcement discretion policies for certain categories of IVDs manufactured by a laboratory, as explained in more detail in sections V.B. and V.C. For example, as proposed in the NPRM, FDA generally does not intend to enforce requirements under the FD&C Act and FDA's regulations for “1976-Type LDTs” (as described in section V.B.1); Human Leukocyte Antigen (HLA) tests that are designed, manufactured, and used within a single laboratory certified under CLIA that meets the requirements to perform high-complexity histocompatibility testing when used in connection with organ, stem cell, and tissue transplantation to perform HLA allele typing, for HLA antibody screening and monitoring, or for conducting real and “virtual” HLA crossmatch tests; and tests intended solely for forensic (law enforcement) purposes (88 FR 68006 at 68022).

In addition, FDA considered comments received on the proposed phaseout policy and, based in part on those comments, made various changes to the phaseout policy, which include the addition of the following enforcement discretion policies:

• FDA intends to exercise enforcement discretion and generally not enforce requirements for LDTs manufactured and performed within the Veterans Health Administration (VHA) or the Department of Defense (DoD);

• FDA intends to exercise enforcement discretion and generally not enforce premarket review requirements for LDTs approved by NYS CLEP;

15

15

For purposes of this preamble, FDA uses the phrase “LDTs approved by NYS CLEP” to refer to LDTs that are approved, conditionally approved, or within an approved exemption from full technical documentation, under NYS CLEP. These three categories of LDTs are discussed further below in section V.B.2. Other LDTs, including “LDTs used in Clinical Trials” and “Tests Not Subject to Evaluation” which are described on NYS CLEP's website (Ref. 24), are not considered “LDTs approved by NYS CLEP” and are not within the enforcement discretion policy with respect to premarket review requirements described in section V.B.2. For additional discussion of the NYS CLEP premarket review program, see section V.B.2.

• FDA intends to exercise enforcement discretion and generally not enforce premarket review requirements and QS requirements (except for requirements under part 820, subpart M (Records))

16 17

for LDTs manufactured and performed by a

laboratory integrated within a healthcare system to meet an unmet need of patients receiving care within the same healthcare system;

16

When the final rule to amend part 820 takes effect in February 2026, the comparable requirements can be found in International Organization for Standardization (ISO) 13485 subclause 4.2 as modified by part 820.

17

FDA recognizes that part 820, subpart M (Records) includes cross-references to §§ 820.20, 820.22, 820.40, and 820.50 (21 CFR 820.20, 820.22, 820.40, and 820.50). For the categories of IVDs discussed in section V.B.3 of this preamble, FDA generally expects compliance with requirements under subpart M but not §§ 820.20, 820.22, 820.40, and 820.50, or comparable provisions of ISO 13485 in accordance with the amendments to part 820 once that rule takes effect in February 2026.

• FDA intends to exercise enforcement discretion and generally not enforce premarket review and QS requirements (except for requirements under part 820, subpart M (Records)) for currently marketed IVDs offered as LDTs that were first marketed prior to the date of issuance of this rule and that are not modified, or that are modified in certain limited ways as described in section V.B.3; and

• FDA intends to exercise enforcement discretion and generally not enforce premarket review and QS requirements (except for requirements under part 820, subpart M (Records)) for non-molecular antisera LDTs for rare red blood cell (RBC) antigens where such tests are manufactured and performed in blood establishments, including transfusion services and immunohematology laboratories and where there is no alternative available to meet the patient's need for a compatible blood transfusion.

These enforcement policies do not apply to any IVDs identified in section V.A.2 as falling outside the scope of the phaseout policy or as discussed in section V.B.

IV. Legal Authority

FDA is issuing this final rule under the Agency's general rulemaking authorities and statutory authorities relating to devices. These authorities include sections 201(h)(1), 301, 501, 502, 510, 513, 514, 515, 518, 519, 520, 701, 702, 704, and 801 of the FD&C Act and section 351 of the PHS Act. In particular:

• Under section 201(h)(1) of the FD&C Act, a device is defined as “an instrument, apparatus, implement, machine, contrivance, implant, in vitro reagent, or other similar or related article, including any component, part, or accessory, which is (A) recognized in the official National Formulary, or the United States Pharmacopeia, or any supplement to them, (B) intended for use in the diagnosis of disease or other conditions, or in the cure, mitigation, treatment, or prevention of disease, in man or other animals, or (C) intended to affect the structure or any function of the body of man or other animals, and which does not achieve its primary intended purposes through chemical action within or on the body of man or other animals and which is not dependent upon being metabolized for the achievement of its primary intended purposes.”

• Section 701(a) of the FD&C Act authorizes FDA to issue regulations for the efficient enforcement of the FD&C Act.

For additional descriptions of some of the authorities referenced above, see section III.A of this preamble. For additional discussion of how these legal authorities apply to LDTs, see the “Legal Basis for the Amendment” section (section V.B) of the NPRM (88 FR 68006 at 68017) and sections VI.D and VI.E of this preamble.

V. Phaseout Policy

Based on the considerations set forth in the NPRM and this preamble, including the public comments discussed in section VI.F below, FDA is phasing out the general enforcement discretion approach for LDTs in stages, as described in more detail below. FDA's intent is that following a 4-year phaseout period, IVDs offered as LDTs generally will be expected to meet applicable requirements, with several enforcement discretion policies for certain categories of IVDs manufactured by a laboratory as discussed further below.

We note that these policies may not be the only enforcement discretion policies applicable to these IVDs, and other enforcement discretion policies not addressed in this phaseout policy may apply to certain IVDs. As discussed in the NPRM, FDA has adopted and intends to continue adopting enforcement discretion policies for certain types of IVDs in certain circumstances, as appropriate (88 FR 68006 at 68021). For example, FDA issued final guidance documents with enforcement discretion policies for certain COVID-19 and mpox tests at the beginning of each declared emergency and, concurrent with this final rule, is issuing a draft guidance document with an enforcement policy for certain IVDs for immediate response to a chemical, biological, radiological, or nuclear (CBRN) agent in the absence of a declaration under section 564 of the FD&C Act (21 U.S.C. 360bbb-3).

Although FDA is phasing out its current general enforcement discretion approach over a period of years, the phaseout policy does not in any way alter the fact that it is illegal to offer IVDs without complying with applicable requirements. Regardless of the phaseout timeline and enforcement discretion policies for certain IVDs discussed below, FDA retains discretion to pursue enforcement action for violations of the FD&C Act at any time, and intends to do so when appropriate.

The details of FDA's final phaseout policy, including the scope, subsidiary enforcement discretion policies, and stages, are set forth below.

A. Scope

1. IVDs Within the Scope of the Phaseout Policy

While FDA's general enforcement discretion approach has been focused on LDTs,

18

FDA has determined to apply a broader scope for the phaseout policy, consistent with FDA's proposal in the NPRM (88 FR 68006 at 68021).

19

Specifically, the phaseout policy applies to IVDs that are

manufactured and offered

as LDTs by laboratories that are certified under CLIA and that meet the regulatory requirements under CLIA to perform high complexity testing, and used within such laboratories,

20

even if those IVDs do not fall within FDA's traditional understanding of an LDT because they are not designed, manufactured, and used within a single laboratory. Throughout this preamble, these IVDs are referred to as “IVDs offered as LDTs.”

21

FDA is adopting this scope because it recognizes that not all laboratories have understood the limited nature of FDA's general enforcement discretion approach and have been offering IVDs based on the approach even when those IVDs do not fit what FDA generally considers to be an LDT. FDA has determined that this

approach will help facilitate uniform compliance going forward.

18

As discussed elsewhere in this preamble, FDA has generally considered the term “laboratory developed test (LDT)” to mean an IVD that is intended for clinical use and that is designed, manufactured, and used within a single CLIA-certified laboratory that meets the regulatory requirements under CLIA to perform high complexity testing.

19

However, certain enforcement discretion policies described in sections V.B and V.C apply only to LDTs.

20

Other laboratories would be out of compliance with CLIA regulations if they were developing and performing tests that are not FDA authorized. Such tests have never fallen within FDA's general enforcement discretion approach (see,

e.g.,

Refs. 25-27).

21

We note that “IVDs offered as LDTs” does not include IVDs manufactured or used

outside

of a laboratory, including collection devices. FDA's statements and actions have shown that the Agency has expected compliance where, for example, CLIA is inapplicable (

e.g.,

manufacturing outside of a laboratory and collection devices).

See, e.g.,

61 FR 10484 (“

in-house

developed tests have not been actively regulated by the Agency”) (emphasis added); Ref. 23 (describing an LDT as an IVD that is “designed, manufactured, and

used

within a single laboratory”) (emphasis added);

United States

v.

Undetermined No. of Unlabeled Cases,

21 F.3d 1026 (10th Cir. 1994) (FDA enforcement action against a laboratory that “purchased specimen containers, repackaged them into kits which included instruction sheets, and forwarded them along with consent forms to insurers to collect specimens”); Ref. 28 (compliance action regarding a blood lead testing system manufactured outside of a laboratory but for use by a laboratory); Ref. 29 (compliance action involving a laboratory and a sample collection kit).

2. IVDs Outside the Scope of the Phaseout Policy

Although FDA is adopting a broader scope for the phaseout policy, it does not intend to sweep in certain IVDs that were excluded from the general enforcement discretion approach, as reflected in compliance patterns, multiple public FDA actions and communications, or both. In particular, the general enforcement discretion approach has never applied to the following tests:

a. Tests that are intended as blood donor screening or human cells, tissues, and cellular and tissue-based products (HCT/P) donor screening tests required for infectious disease testing under § 610.40 (21 CFR 610.40) and § 1271.80(c) (21 CFR 1271.80(c)), respectively, or required for determination of blood group and Rh factors under § 640.5 (21 CFR 640.5).

Under the cited regulations, a blood or HCT/P establishment must not use a test for the purposes listed here unless the test is authorized by FDA for such use. Blood and HCT/P establishments must register with FDA and are subject to FDA inspection (see parts 207, 607, 807, and 1271 (21 CFR parts 207, 607, 807, and 1271)). FDA's general enforcement discretion approach for LDTs has never applied to these tests because these tests are a critical part of the overall process of ensuring the safety of blood and blood components and HCT/Ps by preventing infectious disease transmission and incompatible blood transfusions which can have life-threatening consequences (see,

e.g.,

Refs. 30 and 31). Based on FDA experience, establishments have been generally complying with the requirements to use authorized tests under §§ 1271.80(c), 610.40, and 640.5. FDA addresses comments related, in part, to this category of tests in sections VI.L.14 and VI.L.15.

b. Tests intended for emergencies, potential emergencies, or material threats declared under section 564 of the FD&C Act.

After all previous declarations under section 564(b), FDA has generally expected LDTs to comply with applicable requirements in the FD&C Act and FDA regulations. FDA's general enforcement discretion approach has not applied to these tests because of the significant risk posed by the disease (as signified by the unusual step of issuing a declaration) and because false results can have serious implications for disease progression and public health decision-making, in addition to the individual patient's care. As it has done in other areas, FDA has adopted (and may continue to adopt) specific enforcement discretion policies for such tests (see,

e.g.,

Refs. 32 and 33). In addition, consistent with the Government Accountability Office (GAO)'s 2022 recommendation that “FDA should develop a policy for the use of enforcement discretion regarding unauthorized tests in future public health emergencies” (Ref. 34), FDA is issuing a draft guidance document, concurrent with this final rule, on factors to consider in adopting such enforcement discretion policies. FDA has communicated its expectations regarding tests for emergency use in final guidance and elsewhere, including “It has come to our attention” letters posted on FDA's website and other public communications (see,

e.g.,

Refs. 27, 32 to 37). FDA addresses comments related, in part, to this category of tests in section VI.L.10.

c. Direct-to-consumer tests.

FDA's general enforcement discretion approach has not applied to tests intended for consumer use (without meaningful involvement by a licensed healthcare professional), given the greater risks to patients presented by these tests (see,

e.g.,

Refs. 28 and 39 to 44). FDA's enforcement discretion approach for LDTs was originally premised, in part, on the participation of medical professionals to help determine whether a particular test was appropriate, counsel patients on the significance and limitations of a test, assist in interpreting results, assess how the results fit in the overall clinical picture, and consider next steps. When patients order tests, receive results, or make decisions (such as a decision to stop medication) without this expert intermediary, there is a heightened need for FDA oversight. FDA addresses comments related, in part, to this category of tests in section VI.L.1.

For these categories of tests, FDA has generally expected applicable requirements to be met, and we are not changing that approach with the phaseout policy. FDA intends to continue to enforce all applicable requirements for these categories of tests. Neither the phaseout policy nor any subsidiary enforcement discretion policies described in sections V.B and V.C apply to these tests.

Finally, as further discussed in the NPRM, tests manufactured and offered for use exclusively for public health surveillance are distinct from other tests where: (1) they are intended solely for use on systematically collected samples for analysis and interpretation of health data in connection with disease prevention and control and (2) test results are not reported to patients or their healthcare providers (88 FR 68006 at 68023). The results of these tests are generally used for trending on a population basis or public health outbreaks, where the test results are not intended for clinical decision making. FDA received several comments on these tests (see section VI.L.6), and for the reasons discussed in the NPRM (88 FR 68006 at 68023) and in our responses to those comments, we continue to believe that these tests should not be affected by the phaseout policy.

22

22

Surveillance tests are not used for individual decision-making. Screening tests are distinct from public health surveillance tests and do fall within the phaseout policy.

B. Enforcement Discretion Policies

FDA is phasing out the general enforcement discretion approach for LDTs so that IVDs manufactured by laboratories will generally fall under the same enforcement approach as other IVDs. For certain IVDs, however, FDA intends to exercise enforcement discretion and generally not enforce all or some applicable requirements, for the reasons discussed further below. Specifically, and as described further in section V.B.1, FDA intends to exercise enforcement discretion and generally not enforce all applicable requirements for 1976-Type LDTs, certain HLA tests, tests intended solely for forensic (law enforcement) purposes, and LDTs manufactured and performed within DoD or VHA. As described further in section V.B.2, FDA also intends to exercise enforcement discretion and generally not enforce premarket review requirements for LDTs that are approved by NYS CLEP. In addition, and as described further in section V.B.3, FDA intends to exercise enforcement discretion and generally not enforce premarket review and QS requirements (except for requirements under part 820, subpart M (Records)) for LDTs manufactured and performed by a laboratory integrated within a healthcare system to meet an unmet need of patients receiving care within the same healthcare system, currently marketed IVDs offered as LDTs, and certain non-molecular antisera LDTs for rare RBC antigens.

As noted above, these policies do not apply to the tests described in section V.A.2. Moreover, in an emergent situation (see additional discussion of this time period below), these policies do not apply to tests that are: (1) intended to detect or diagnose a serious or life-threatening disease or condition that may be attributed to a newly identified, previously unknown, or

unusual CBRN agent or agents; or a known agent or agents that results in a newly identified or unusual clinical presentation of such a disease or condition; and (2) needed for immediate response to a potential case or cases of such disease or condition for which there is no adequate, authorized, and available alternative. FDA is proposing a separate enforcement policy for some such tests in a concurrently issued draft guidance entitled “Enforcement Policy for Certain In Vitro Diagnostic Devices for Immediate Public Health Response in the Absence of a Declaration under Section 564.” As discussed in that draft guidance, that proposed enforcement policy would be for tests that are intended to help ensure the government's coordinated and effective public health response and so is limited to certain tests and certain laboratories, such as those that are U.S. Government (USG) laboratories, State or local public health laboratories, or other laboratories that have agreements with the USG.

23

FDA believes that the proposed policy in that draft guidance (and not the enforcement discretion policies described in section V.B of this preamble) would be appropriate for such tests during the limited time period described in the draft guidance—specifically, during an emergent situation.

24

We note that prior to an emergent situation and after an emergent situation has been resolved, when there is not a critical need for a coordinated and immediate public health response and where the implications of false results may not have as serious implications for public health decision-making, such tests may fall within the enforcement discretion policies described in section V.B of this preamble.

23

For tests that meet the description included at the beginning of this paragraph but that would not otherwise fall within the proposed policy described in the draft guidance because, for example, they are manufactured by entities that fall outside the scope of the draft guidance, FDA is not proposing an enforcement discretion policy in the draft guidance. For such tests, FDA generally will expect compliance with applicable FDA requirements in line with the phaseout policy during an emergent situation, and outside of an emergent situation, these tests could potentially fall within an enforcement discretion policy described in section V.B. of this preamble.

24

Prior to finalization of that draft guidance, FDA intends to act consistent with the relevant policies for LDTs included in this final rule and will consider whether to update any policies herein as a result of any changes to the proposed enforcement policy described in the draft guidance, when finalized.

As with any enforcement discretion policy, FDA may update any of these policies as circumstances warrant or if the circumstances that inform these policies change, consistent with FDA's good guidance practices (21 U.S.C. 371(h), § 10.115). Notably, these enforcement discretion policies do not confer lawful marketing status on any IVD being marketed as described in the policies. These policies do not in any way alter the fact that it is illegal to market an IVD that lacks required premarket authorization or is otherwise in violation of the FD&C Act, the PHS Act, or FDA regulations. These policies set forth FDA's general priorities and, consistent with FDA's public health mission, FDA intends to take action to enforce applicable requirements for IVDs (including IVDs described in these policies) as appropriate, taking into account any public health concerns as evaluated on a case-by-case basis.

25

For example, if FDA receives reports, or otherwise learns of information, that raise safety or effectiveness concerns with an IVD that falls within an enforcement discretion policy, FDA generally intends to take action with respect to requirements applicable to that specific IVD.

25

See Heckler

v.

Chaney,

470 U.S. 821, 835 (1985) (providing that the FD&C Act's enforcement provisions commit broad discretion to the Secretary to decide how and when they should be exercised).

1. Enforcement Discretion Policies With Respect to All FDA Requirements

For several categories of tests, FDA intends to continue the general enforcement discretion approach and generally not enforce any applicable requirement because tests in these categories are, in our experience, unlikely to pose significant risks or are conducted in circumstances that themselves will mitigate the risks. One such category of tests is referred to in this preamble as “1976-Type LDTs.” Such tests have the following characteristics common among LDTs offered in 1976: (1) use of manual techniques (without automation) performed by laboratory personnel with specialized expertise; (2) use of components legally marketed for clinical use; and (3) design, manufacture, and use within a single CLIA-certified laboratory that meets the requirements under CLIA for high complexity testing. The characteristics associated with LDTs offered in 1976 resulted in the emergence of FDA's general enforcement discretion approach for LDTs, and the specific characteristics listed above provide the greatest risk mitigation among the characteristics that were commonly associated with LDTs offered in 1976 (discussed in section III). Based on changes to the LDT landscape since 1976, the risks associated with most modern LDTs are generally much greater today than they were in 1976; however, for tests that share the characteristics listed above, FDA has determined that the risks are sufficiently low such that FDA's general enforcement discretion approach for LDTs should continue to apply (see section VI.L.3 for a discussion of the comments on this topic and FDA's responses to those comments). These tests might include, for example, immunohistochemistry tests that involve no automated preparation or interpretation, but would not include, for example, lateral flow tests, as they do not generally rely on laboratory personnel expertise. This enforcement discretion policy does not apply to any IVDs identified in section V.A.2 as falling outside the scope of the phaseout policy or as discussed in section V.B. FDA intends to consider whether guidance containing additional discussion and examples of tests that may fall within this category would be helpful, and would issue any such guidance in accordance with good guidance practices (see § 10.115).

Another category of such tests is HLA tests that are designed, manufactured, and used within a single laboratory certified under CLIA that meets the requirements to perform high-complexity histocompatibility testing when used in connection with organ, stem cell, and tissue transplantation to perform HLA allele typing, for HLA antibody screening and monitoring, or for conducting real and “virtual” HLA crossmatch tests (hereinafter “HLA tests for transplantation”). Physicians must often make prompt decisions about transplantation based on medical judgment regarding their patient's condition and degree of mismatch between the donor and patient should an organ, stem cells, or tissue become available. Because new alleles are continuously identified, and the need for assessing degree of crossmatch is generally urgent, modifications to HLA tests for transplantation are often made rapidly in response to urgent situations. Further, these tests are often individualized within each medical facility; for example, they include reagents that reflect local HLA polymorphisms and patient demographics.

In addition, oversight under certain Federal programs helps to mitigate the risks of harm from inaccurate and unreliable HLA tests for transplantation. For example, the National Organ Transplant Act (NOTA) of 1984 created the Organ Procurement and Transplant Network (OPTN). NOTA, as amended (42 U.S.C. 273

et seq.

), and the OPTN

Final Rule, 42 CFR part 121, establish a comprehensive system for the safe and equitable allocation, distribution, and transplantation of donated organs. The OPTN Final Rule and OPTN bylaws and policies govern operation of all member transplant hospitals, organ procurement organizations, and histocompatibility laboratories in the United States. The Stem Cell Therapeutic and Research Act of 2005 (Pub. L. 109-129), as amended, authorizes a national registry (“Be the Match Registry”) to support patients in need of bone marrow or umbilical cord blood transplants, which is operated under Federal contracts by the National Marrow Donor Program® (NMDP) (Ref. 45). NMDP sets forth minimum requirements for organizations working through the NMDP to facilitate stem cell transplants (Refs. 46 and 47).

OPTN has requirements for performance of HLA typing, antibody screening, and crossmatching tests, and NMDP requires HLA typing for donors and potential recipients for stem cell transplants facilitated by the Be the Match Registry, as well as reporting of test results to NMDP (Refs. 47 and 48). Both OPTN and NMDP have procedures in place for identifying, investigating, and reporting discrepant tests results (Refs. 48 and 49).

In addition to these safeguards designed to identify and resolve potentially inaccurate results, each OPTN member histocompatibility laboratory must, among other things, meet specified American Society for Histocompatibility and Immunogenetics (ASHI) and/or College of American Pathologists (CAP) standards as a condition of OPTN membership (Ref. 50). NMDP similarly requires histocompatibility laboratories used by U.S. transplant centers and donor centers to be accredited by CAP and/or ASHI (Refs. 46, 51 and 52). Both ASHI and CAP standards have provisions that specifically address OPTN and/or NMDP requirements for histocompatibility laboratories that perform tests for those programs. Importantly, as discussed below, FDA does not believe that a CAP or ASHI accreditation of a laboratory, on its own, is sufficient to mitigate risk and provide assurance of the safety and effectiveness for all IVDs offered as LDTs by the accredited laboratory. However, we consider the fact that OPTN and NMDP require adherence to CAP and/or ASHI standards, including provisions specific to OPTN and NMDP requirements, to be one factor that helps mitigate risk of inaccurate results or unreliable HLA tests for transplantation. After considering this factor in combination with the protections provided through the programs described above and the urgent circumstances in which HLA tests for transplantation may be modified and performed, as well as the comments received on our proposed approach to HLA tests for transplantation, FDA intends to continue the general enforcement discretion approach for these tests. We note that this enforcement discretion policy does not apply to HLA tests used for blood transfusion, which are highly standardized across institutions, nor does it apply to any IVDs identified in section V.A.2 as falling outside the scope of the phaseout policy or as discussed in section V.B.

An additional category of such tests is tests intended solely for forensic (law enforcement) purposes. FDA has had an enforcement discretion approach for such tests for over 20 years and that approach applies to such tests regardless of whether they are offered as an LDT.

See, e.g.,

65 FR 18230, April 7, 2000. Tests used in the law enforcement setting are subject to protections and requirements associated with the judicial process that mitigate risk related to test accuracy and sample collection and that generally are not available in the home, workplace, insurance, and sports settings. These protections include the use of rules of evidence in judicial proceedings and legal representation of the accused (

i.e.,

the person being tested) through the judicial process during which the accuracy of the test may be raised during the adjudication. This enforcement discretion policy does not apply to any IVDs identified in section V.A.2 as falling outside the scope of the phaseout policy or as discussed in section V.B.

A final category of such tests is LDTs

26

manufactured and performed within DoD or VHA. This policy applies only to LDTs used for patients that are being tested and treated within the DoD or VHA. In the NPRM, FDA sought comment on whether it would be appropriate to continue the general enforcement discretion approach, such that FDA generally would not enforce any applicable device requirements, “where outside programs can be leveraged” (88 FR 68006 at 68024). FDA mentioned programs within VHA as an example, and we received several comments stating that FDA should continue the general enforcement discretion approach for LDTs manufactured and performed by VHA, generally on the grounds that it would avoid “duplicating regulatory oversight regimes” and promote the efficient use of resources. Two comments suggested that FDA should not continue the general enforcement discretion approach for LDTs manufactured and performed by VHA because VHA's program is not in alignment with FDA regulation (though one of these comments supported “leveraging” outside programs “in principle”). FDA received one comment, submitted by DoD, which stated that FDA should maintain an enforcement discretion approach for LDTs “utilized by DoD for our service members.” Among other things, DoD emphasized “the importance of LDTs to DoD's operational readiness and mission success,” and referenced DoD's internal programs, including “the authority, oversight, and responsibilities vested in the Assistant Secretary of Defense (Health Affairs).”

26

Consistent with what FDA has generally considered to be an LDT (as discussed elsewhere in this preamble), this enforcement discretion policy applies only to tests that are designed, manufactured, and used within a single CLIA-certified laboratory that meets the requirements under CLIA for high complexity testing.

FDA recognizes that DoD and VHA have statutory mandates under 10 U.S.C. chapter 55 and 38 U.S.C. chapter 73 to provide for the care of specific populations in their systems and have existing oversight and enforcement groups within their respective systems. Based on consultation with DoD and VHA, FDA understands that both departments use and will continue to use FDA-authorized IVDs wherever available. However, to meet the needs of their patient populations (

i.e.,

military personnel, veterans, and their families) and fulfill their mandates, DoD and VHA often manufacture unique LDTs, such as tests for diseases or chemicals to which their patients may be exposed while serving abroad but which do not exist at home. DoD and VHA have developed expertise for evaluating these unique tests, and are taking steps in consultation with FDA to track all LDTs in their systems and to ensure the analytical and clinical validity of their LDTs, the quality manufacturing of their LDTs, and the central reporting of adverse events.

27

Additional oversight by FDA would not be an efficient use of government resources in these circumstances.

27

To the extent that VHA and DoD anticipate the need for additional resources, FDA understands that such matters will be addressed through the management of those departments.

This enforcement discretion policy does not apply to any IVDs identified in section V.A.2 as falling outside the scope of the phaseout policy or as discussed in section V.B.

2. Enforcement Discretion Policies With Respect to Premarket Review Requirements

FDA also generally intends to exercise enforcement discretion with respect to premarket review requirements for LDTs

28

that are approved by NYS CLEP.

29

For these LDTs, FDA intends to exercise enforcement discretion and generally not enforce premarket review requirements given certain risk mitigations under NYS CLEP as discussed further below. This policy applies only to the approved version of the test (FDA is aware that some laboratories may offer different versions of an LDT depending on whether a patient specimen comes from NYS or from elsewhere). This enforcement discretion policy does not apply to any IVDs identified in section V.A.2 as falling outside the scope of the phaseout policy or as discussed in section V.B.

28

Consistent with what FDA has generally considered to be an LDT (as discussed elsewhere in this preamble), this enforcement discretion policy applies only to tests that are designed, manufactured, and used within a single laboratory that is certified under CLIA and meets the regulatory requirements under CLIA to perform high complexity testing.

29

As noted elsewhere in this preamble, for purposes of this preamble FDA uses the phrase “LDTs approved by NYS CLEP” to refer to LDTs that are approved, conditionally approved, or within an approved exemption from full technical documentation, under NYS CLEP. These three categories of LDTs are discussed further below in this section (section V.B.2). Other LDTs, including “LDTs used in Clinical Trials” and “Tests Not Subject to Evaluation” which are described on NYS CLEP's website (Ref. 24), are not considered “LDTs approved by NYS CLEP” and are not within the enforcement discretion policy with respect to premarket review requirements described in this section.

FDA intends to phase out the general enforcement discretion approach with respect to other applicable requirements for these tests consistent with the stages described in section V.C below. In brief, for these tests, FDA intends at stage 1 to phase out the general enforcement discretion approach with respect to MDR requirements, correction and removal reporting requirements, and QS requirements under § 820.198 (complaint files) 1 year after publication of this final rule; at stage 2 to phase out the general enforcement discretion approach with respect to requirements not addressed in the other stages (these requirements include,

e.g.,

registration and listing requirements and labeling requirements) 2 years after publication of this final rule; and at stage 3 to phase out the general enforcement discretion approach with respect to certain QS requirements (see below for further discussion) 3 years after publication of this final rule. See section V.C for further information.

As noted above, in the NPRM, FDA sought comment on whether it would be appropriate to continue the general enforcement discretion approach with respect to LDTs that are under NYS CLEP or certain other programs (88 FR 68006 at 68024), and we received several comments in response (see discussion in section VI.F.5 of this preamble). This policy reflects consideration of those comments. Should experience with this policy indicate that changes are warranted, FDA would consider appropriate policy changes through guidance in accordance with good guidance practices (see § 10.115).

FDA believes that NYS CLEP has a program that provides for certain mitigations that help reduce the risk of harm from inaccurate and unreliable LDTs. Specifically, as discussed further below, NYS CLEP has a program under which high risk and moderate risk LDTs generally are evaluated for analytical and clinical validity. Based on the available information, FDA believes that generally NYS CLEP's review of analytical and clinical validity of LDTs helps to mitigate the risk of harm from inaccurate and unreliable LDTs and that, rather than enforcing premarket review requirements by FDA, it would be more efficient and effective to use our resources for other oversight activities regarding IVDs offered as LDTs.

Under NYS CLEP's program, high risk LDTs require full technical review and approval prior to testing on specimens from NYS (Ref. 53). Moderate risk LDTs require full technical review but may receive conditional approval if the laboratory holds a permit in the appropriate category (Ref. 53). For classification as a moderate risk LDT under NYS CLEP, certain criteria must be met,

e.g.,

the LDT uses well-established methodology (as defined by NYS CLEP, this includes, among other things, the laboratory having demonstrated competence for development of LDTs of the same or similar technology through multiple prior high-quality submissions) (Ref. 53). Upon notification of a moderate risk classification and conditional approval, the laboratory may offer the test (Ref. 53). Once the full technical review has been completed, the moderate risk LDT may receive approval (Ref. 53). For additional information, see NYS CLEP's Tiered Evaluation of Laboratory Developed Tests Policy (Ref. 53).

In its enforcement discretion policy with respect to premarket review requirements, FDA is including not just those moderate risk LDTs that receive full approval by NYS CLEP but also those that receive conditional approval by that agency. For LDTs receiving conditional approval, full technical review is pending and these tests may receive approval by NYS CLEP once their review has been completed. FDA does not intend to use its resources to enforce premarket review requirements for these LDTs that are under review by NYS CLEP and may eventually receive approval. However, if an LDT has its conditional approval withdrawn by NYS (

e.g.,

because approval is denied after NYS CLEP completes the full technical review), the LDT would no longer be under this enforcement discretion policy as it would neither have conditional approval nor full approval.

30

30

Although not relevant to our decision-making with respect to our policy regarding LDTs approved by NYS CLEP, it is our understanding, based on consultation with NYS CLEP, that withdrawal of conditional approval due to approval being denied after NYS CLEP completes the full technical review is a rare occurrence.

For purposes of full technical review (as mentioned above, this applies to high risk and moderate risk LDTs), NYS CLEP requires the submission of detailed information as specified in the applicable checklist (either the general checklist or test-specific checklist) (Ref. 24). For example, under the general checklist, laboratories must submit, among other things, a description of the test target, data supporting analytical validity, data supporting clinical validity, sample test reports, standard operating procedures, and other information regarding the subject test (Ref. 54). Additionally, laboratories must submit a “Risk Attestation Form for Laboratory Developed Tests” containing additional information about the test, including a summary of intended use (including target population, methodology and technology, specimen types, and whether the intend use makes claims or direct reference to recognized diseases/conditions), whether the laboratory has full approval of other LDTs using the same test method that is used for the proposed new test, whether the methodology is well-established in the laboratory and generally accepted by the field, evidence of clinical validity, and information regarding the potential impact of an inaccurate test result (Ref. 55).

NYS CLEP also has a process for laboratories to request an exemption from full technical documentation. As described on NYS CLEP's website, “[o]nce acceptable method validation performance has been demonstrated by the NYS approval of a representative sampling of tests that utilize a

methodology that is common across many analytes/targets, the laboratory may request an exemption from the requirement to submit full method validation documentation for future test/assays that utilize the same methodology” (Ref. 24). An application for an exemption from full technical documentation must include: a written request for an exemption that identifies “the previously submitted tests to be used as the predicate submissions for the exemption”; “a standardized protocol for method validation to include a description of the laboratory's principles and practices for assay development and initial validation”; and “laboratory-specific protocols for on-going validation, including quality control procedures and quality assurance indicators” (Ref. 24). If an exemption is approved, then a streamlined process applies to new LDTs with the same methodology under the exemption. For such new LDTs, certain information must be provided, including data on analytical and clinical validity, but this can be provided in summary form (see the Add Under Exemption Form available on NYS CLEP's website, Ref. 24). The summary of the validation studies performed must address how analytical and clinical performance characteristics were established (see the Add Under Exemption Form available on NYS CLEP's website, Ref. 24). Additionally, for such new LDTs, laboratories must submit sample reports for all applicable findings (see the Add Under Exemption Form available on NYS CLEP's website, Ref. 24), a “Risk Attestation Form for Laboratory Developed Tests” containing additional information about the test, including information regarding the potential impact of an inaccurate test result (Ref. 55), and certain other information if applicable (Ref. 24). Although specific approval of new LDTs added under an approved exemption is not required, it is our understanding that NYS CLEP reviews the information submitted for these LDTs. Further, NYS CLEP reserves the right to rescind an exemption at any time (Ref. 24). Because NYS CLEP reviews the analytical and clinical validity of LDTs that are added under an approved exemption and may rescind an exemption at any time, FDA is including such LDTs within the enforcement discretion policy with respect to LDTs approved by NYS CLEP.

Based on the available information as discussed above, FDA believes that generally NYS CLEP's review of analytical and clinical validity of LDTs helps to mitigate the risk of harm from inaccurate and unreliable LDTs. First, NYS CLEP reviews much of the same information that FDA reviews in assessing analytical and clinical validity (

e.g.,

data supporting analytical validity, data supporting clinical validity, sample test reports, and standard operating procedures). For example, in comments submitted to the docket for this rulemaking, NYS CLEP explained, “Applications must include validation data throughout the reportable range, particularly at or near the limit of detection, and for intended specimen types, specimen stability range, clinical indications, and target populations (pediatric vs adult, symptomatic vs asymptomatic, varied ethnicities, etc.).” Second, NYS CLEP is identifying many of the same types of issues that FDA has identified with LDTs. In their comments, NYS CLEP provided a detailed description of the issues they have identified when reviewing LDT applications. For example, NYS CLEP noted that more than half of the LDTs submitted for their review cannot be approved based on the original application. For such applications, NYS CLEP requests additional information, sometimes multiple times, to address a range of issues, including “design flaws, inadequate validation data, and process problems that call into the question the reliability of the results.” These are the same types of issues FDA has observed in the review of emergency use authorization (EUA) requests from laboratories for molecular tests for COVID-19 (see Ref. 18) and in other premarket submissions for LDTs (see Ref. 16). Additionally, FDA collaborated with NYS CLEP in the review of the first authorized tumor profiling test and found substantial alignment in FDA's and NYS CLEP's assessments of the analytical and clinical validity of this LDT for tumor profiling. FDA has also accredited NYS CLEP as a Third Party Review Organization accredited under FDA's Third Party review program (3P510K Review Organization) qualified to conduct reviews of 510(k)s for certain IVDs. Accreditation of 3P510K Review Organizations is based on many factors, including qualification of staff in the scientific disciplines relevant to the review of the specific device types that the 3P510K Review Organization intends to review (Ref. 56). In the case of IVDs, the 3P510K Review Organization must be qualified to assess the analytical and clinical validity of tests which NYS CLEP was able to demonstrate.

Exercising enforcement discretion with respect to the premarket review requirements for LDTs approved by NYS CLEP will facilitate more efficient use of FDA resources. The resources that FDA would otherwise spend on premarket review of such LDTs can instead be focused on premarket review of other IVDs offered as LDTs and enforcement of other applicable requirements. FDA estimates that 12.1 percent of IVDs offered as LDTs would not experience new costs associated with submission preparation and review as a result of the enforcement discretion policy with respect to LDTs approved by NYS CLEP, as discussed in appendix A of the FRIA (Ref. 10).

As mentioned above, FDA intends to phase out the general enforcement discretion approach with respect to other applicable requirements for LDTs approved by NYS CLEP, consistent with the stages described below in section V.C. Enforcement of other requirements will help to protect and promote the public health,

e.g.,

by providing FDA and the public with important information about these tests. For example, compliance with registration and listing requirements will provide FDA and the public with basic information on these LDTs, and compliance with MDR requirements will provide FDA and the public with adverse event information about these LDTs. Further, under § 807.26(e) (21 CFR 807.26(e)) (additional device listing information), FDA intends to request the labeling for these LDTs, which will provide information on test performance and a summary of the supporting validation, among other things.

31

Additionally, compliance with labeling requirements, including those in § 809.10(b)(12), will help to ensure that healthcare providers and patients have information on test performance, among other things, and thus enable more informed decision making. The labeling information and adverse event reports will help FDA identify LDTs that raise concerns,

e.g.,

concerns regarding insufficient validation or inaccurate

results. Compliance with the QS requirements that FDA intends to enforce for these LDTs will help provide for quality manufacturing of these tests. As discussed in section V.C, for LDTs, FDA generally will expect compliance at the 3-year mark with some, but not all, of the QS requirements (specifically, design controls, purchasing controls, acceptance activities, corrective and preventive actions (CAPA), and records requirements). This includes for LDTs approved by NYS CLEP. However, it is our understanding, based on consultation with NYS CLEP, that compliance with NYS CLEP's clinical laboratory standards (which exceed CLIA requirements in certain respects) and its premarket review requirements collectively could generally satisfy these subparts of the QSR except as to certain aspects of design control documentation. Therefore, although not relevant to our decision-making with respect to our policy regarding LDTs approved by NYS CLEP, FDA does not anticipate significant additional burden with respect to compliance with these QS requirements for laboratories offering LDTs approved by NYS CLEP.

31

Devices licensed under section 351 of the PHS Act register and list pursuant to part 607 (21 CFR 607.1 and 807.20(e)), which does not contain a provision identical to 21 CFR 807.26(e). Most licensed IVDs are tests intended for use as blood donor screening tests or HCT/P donor screening tests subject to § 610.40 and 1271.80(c), respectively, or tests for determination of blood group and Rh factors subject to § 640.5. As explained in the NPRM (88 FR 68006 at 68021), FDA's general enforcement discretion approach for LDTs has never applied to such tests. Therefore, we anticipate that there would be a limited number of IVDs subject to the registration and listing requirements in part 607 that would fall within this policy or other policies for which FDA intends to request laboratories to provide labeling information in connection with listing the device. Should FDA receive listing information under part 607 for an IVD that is not licensed, we will consider if any additional action is appropriate, including with respect to information regarding IVD performance.

Finally, as noted elsewhere in this preamble, regardless of this or any other enforcement discretion policy, FDA retains discretion to pursue enforcement action at any time against violative IVDs when appropriate. We intend to carefully monitor tests falling within this policy and to take action when appropriate to protect the public health.

3. Enforcement Discretion Policies With Respect to Premarket Review and Certain QS Requirements

FDA also intends to exercise enforcement discretion and generally not enforce premarket review and most QS requirements for three categories of IVDs. These enforcement discretion policies have been added to the final phaseout policy after consideration of comments received on the NPRM.

First, for the reasons discussed further below, FDA intends to exercise enforcement discretion and generally not enforce premarket review requirements and QS requirements (except for requirements under part 820, subpart M (Records))

32

for LDTs manufactured and performed by a laboratory integrated within a healthcare system to meet an unmet need of patients receiving care within the same healthcare system. This enforcement discretion policy does not apply to any IVDs identified in section V.A.2 as falling outside the scope of the phaseout policy or as discussed in section V.B.

32

As noted in footnote 17, for the categories of IVDs discussed in section V.B.3, FDA generally expects compliance with requirements under part 820, subpart M (Records) but not §§ 820.20, 820.22, 820.40, and 820.50 (which are cross-referenced in subpart M), or comparable provisions of ISO 13485 in accordance with the amendments to part 820 once that rule takes effect in February 2026.

In the NPRM, FDA discussed LDTs for unmet needs, stating that a specific enforcement discretion policy for such LDTs was not included in the proposed phaseout policy because we anticipated that programs currently in place (

e.g.,

the Humanitarian Use Devices (HUD)/HDE program and the Breakthrough Devices program) may facilitate the development and premarket authorization of IVDs for unmet needs.

33

See

88 FR 68006 at 68026. We received over 100 comments addressing whether FDA should adopt a specific enforcement discretion policy for LDTs for unmet needs (see section VI.L.5). In particular, we received numerous comments that asserted that the perceived burden of premarket review and QS requirements would lead laboratories to stop developing such LDTs, leaving patients without access to the LDTs they need. For this reason, many comments recommended that FDA adopt an enforcement discretion policy for LDTs for unmet needs. Two public interest groups recommended against adopting a separate policy for LDTs for unmet needs for various reasons, including so that LDTs for patients with unmet needs would have the same assurances of safety and effectiveness as LDTs for other patients. Stakeholders further commented that the existing HUD/HDE and Breakthrough Devices programs are insufficient to mitigate the perceived burden that laboratories face with respect to development of LDTs for unmet needs. Specifically, commenters noted the numerical limit of 8,000 tests nationwide per year is too restrictive, the requirements for use of tests under HDE (

e.g.,

institutional review board approval) dissuade physicians from using them, and the program has only been used for 6 IVDs despite existing for over 30 years. We also received information in comments indicating that laboratories integrated within healthcare systems, including AMCs, often make tests to meet the unique needs of their patients, and that patients may be referred to those systems because of their ability to meet patient needs that cannot be met elsewhere. The comments stated that this is often the case for patients with rare diseases for which the market is so small that there is no financial incentive for non-laboratory manufacturers to meet their needs and for which collecting data to validate a test is particularly challenging due to small patient populations (for example, rare immunohematology problems, Huntington disease, Prader-Willi/Angelman syndrome, and genetic tests for certain cancers).

33

As described in the NPRM, FDA considered a possible premarket-review approach specific to LDTs for unmet needs in the “Discussion Paper on Laboratory Developed Tests (LDTs)” issued by the Agency on January 13, 2017 (2017 Discussion Paper) (Ref. 57) (88 FR 68006 at 68026).

With respect to AMCs in particular, the Agency sought comment in the NPRM on whether FDA should have a different enforcement policy for tests manufactured by AMC laboratories.

See

88 FR 68006 at 68023-24. We asked about various aspects of such a policy, including whether any continued enforcement discretion policy should take into account “whether an FDA cleared or approved test is available for the same intended use as the test manufactured by an AMC laboratory,” and the public health rationale for how integration of a laboratory into patient care might support a different approach for tests manufactured by AMC laboratories.

Id.

at 68024. We received over 100 comments addressing whether FDA should adopt a specific enforcement discretion policy for tests offered by AMC laboratories and/or other laboratories integrated within healthcare systems (see section VI.F.4 of this preamble). Many of the comments we received addressing whether FDA should adopt a specific enforcement discretion policy for LDTs for unmet needs addressed LDTs for unmet needs manufactured by AMC laboratories/other laboratories integrated within healthcare systems. These comments were from patients, healthcare providers, AMCs, other healthcare systems, and various entities representing such groups.

The majority of comments recommended that FDA adopt an enforcement discretion policy specific to tests manufactured by AMC laboratories given risk mitigations provided by the integration of the laboratory within the AMC that is providing care to the patient. Many comments stated that because other laboratories are similarly integrated within healthcare systems, any such enforcement discretion policy should not be limited to AMC laboratories. Many of these comments emphasized the built-in communication mechanisms between the laboratory and AMC/other healthcare system within which the laboratory is integrated. For example:

• “[T]he close connection between the clinical pathologists developing the tests and the care providers at AMCs

further validates the alignment between diagnostic results and clinical presentation and helps to provide real-time feedback to the LDT developers on test performance and outcomes.”

• “As hospital-based labs, we are integrated into patient care within the healthcare system. Treating clinicians will contact us directly when tests don't make sense and we adjust our testing strategies if needed. I personally get around 3-10 questions per week from clinicians as a laboratory medical director. At AMCs, while we implement LDTs we seek information and feedback from our clinical colleagues . . . . This direct connection and information flow allows for quality control and real-time communication if a test is not performing as expected.”

• “As a CLIA director of a hospital-based lab, I occasionally see patients with specimens that were sent to our laboratory as well as an off-site, disconnected reference lab for the same test at nearly the same time. The results are often not consistent. I am able to investigate further by getting a new specimen and communicating with the clinician about the patients' signs, symptoms, and radiology results. I review our other test results, including some of our other LDTs. The reference labs are often not aware of the issues because they do not have the same line of communication and access to the electronic health record. They continue to offer the same test with no knowledge of the problem.”

• “There is a direct connection or ability to directly connect between the laboratory provider/director and the treating clinician, and laboratory professionals have access to patient electronic medical records, details of which often inform the nuance of laboratory testing that is managed locally. This direct connection and information flow allows for quality control that cannot be engendered by an off-site, disconnected reference lab model for testing and allows for issues associated with any particular testing modality to be identified; thus it provides quality control at both the patient and assay level.”

Several comments recommended against a separate enforcement discretion policy for tests manufactured by AMC laboratories, including because they argued that AMC laboratory tests have the same problems as other IVDs (which FDA acknowledged in the context of the COVID-19 pandemic) and having the same enforcement policies for these tests as for other tests will level the playing field and promote the development of new and improved tests.

As an initial matter, we understand that laboratories that develop LDTs for unmet needs, often laboratories integrated within a healthcare system, may be more likely to stop developing many of these LDTs for unmet needs if the proposed phaseout policy were finalized. The cost of compliance with premarket review and QS requirements may be deemed too high given the limited market for many of these LDTs for unmet needs, and so laboratories may not have financial incentives to develop these types of LDTs in particular (for example, FDA's primary estimates anticipate the cost per premarket submission to range from approximately $250,000 to $4.5 million depending on the type of submission required, in addition to costs associated with QS requirements, annual reporting requirements (for PMAs) and applicable user fees, as described in sections II.F.3, II.F.4 and II.H of the FRIA (Ref. 10)). In their comments, various laboratories noted challenges and limitations associated with the HDE pathway that would dissuade them from seeking HDE approval for their LDTs. Specifically, commenters noted the numerical limit of 8,000 tests nationwide per year is too restrictive in that it applies to the cumulative testing volume of all patients who would be tested with a diagnostic device annually, and the requirements for use of tests under HDE (

e.g.,

administration of the test in a facility having oversight by an institutional review board, monitoring whether the national testing volume exceeds 8,000 patients per year, and limitations on profit, etc.) dissuade laboratories from developing such tests and submitting them for HDE approval. Although we think that the HDE pathway could help to facilitate the manufacture and premarket authorization of certain LDTs for unmet needs, based on these comments, we are concerned that many laboratories would stop manufacturing LDTs for unmet needs altogether, instead of seeking HDE approval for the LDTs, in light of the perceived financial costs of premarket review and QS requirements. Moreover, although we think that the Breakthrough Devices program would help to facilitate the premarket review process for LDTs for unmet needs, again based on the comments, we are concerned many laboratories would stop manufacturing LDTs for unmet needs altogether if they are expected to comply with premarket review and QS requirements.

As such, and upon further consideration, FDA has determined that a targeted enforcement discretion policy is appropriate to help avoid patients being deprived of critically needed LDTs where certain risk mitigations exist. Specifically, FDA intends to exercise enforcement discretion and generally not enforce premarket review and QS requirements (except for requirements under part 820, subpart M (Records)) for LDTs manufactured and performed by a laboratory integrated within a healthcare system to meet an unmet need of patients receiving care within the same healthcare system. FDA intends to phase out the general enforcement discretion approach for these LDTs with respect to all other applicable requirements consistent with the stages described in section V.C. Should experience with this policy indicate that changes are warranted, FDA would consider appropriate policy changes through guidance in accordance with good guidance practices (see § 10.115).

This policy is limited to LDTs for patients who are receiving care within the healthcare system within which the laboratory offering the LDT is integrated. FDA does not consider this to include patients that are being treated at an affiliated hospital with different corporate ownership than the laboratory. Where the laboratory and the treating physicians are in the same corporate entity, there is shared responsibility and potential liability for patient outcomes, which helps mitigate risk. Moreover, the policy is limited to LDTs that are ordered by a healthcare practitioner on the staff or with credentials and privileges at a facility owned and operated by the same healthcare system employing the laboratory director and performing the LDT. In these circumstances, FDA believes that the risk mitigations present help to address some of the concerns raised regarding problematic IVDs offered as LDTs discussed in the NPRM and this preamble.

For LDTs manufactured and performed by laboratories integrated within healthcare systems, FDA generally has greater confidence that ordering physicians will communicate any questions about LDTs or concerns regarding the safety and effectiveness of the LDT (

e.g.,

when the patient's symptoms point to another diagnosis; when subsequent test results contradict the original test result) to a laboratory given the built-in communication mechanisms present. Moreover, FDA generally has greater confidence that laboratories will communicate any limitations of the LDT or other relevant information to the ordering physician given these mechanisms. We think this is particularly likely to happen in the context of LDTs for unmet needs, which

are likely to be a focus of attention and communication between laboratorians and providers given the uncommon nature of the issues presented.

Communication from ordering physicians to laboratories may help laboratories to identify any problems with their LDT and make necessary adjustments, improvements, and other changes to the LDT. Although we acknowledge that any identification and subsequent modification of the LDT would happen postmarket, and thus would not prevent potentially problematic LDTs from ever being used, subsequent modification would benefit future patients and providers who are relying on the LDT. In addition, communication from laboratories to ordering physicians may help to underscore to the ordering physicians any limitations with the LDT and provide other relevant information to ordering physicians, for example that is specific to the unique needs of their patient, which in turn should help inform appropriate use and interpretation of the LDT.

34

34

See

Ref. 58 (“more aggressive laboratory involvement in [the interpretation and reporting] step may be necessary to ensure a more nearly perfect hit rate on proper interpretation and action after reporting of laboratory results”);

see also

Ref. 59. Shaw and Miller compared hospital laboratories and hospital-independent reference laboratories, and highlighted the following advantages, among others, of the former over the latter: (1) tracking problems (hospital laboratories “[c]an easily work with medical and nursing services to coordinate patient care efforts” whereas hospital-independent reference laboratories “[c]an only track internal problems effectively”) and (2) physician consultation (this is “[r]eadily available” for hospital laboratories whereas it is “[n]ot as readily available” for hospital-independent reference laboratories).

We believe that generally these features associated with integration of a laboratory within the healthcare system, along with enforcement of other applicable regulatory requirements as described in the phaseout policy (see section V.C), help to mitigate the risk of harm from inaccurate and unreliable LDTs. While we recognize that these features do not mitigate all risk and there may still be some uncertainty about the performance of LDTs that fall within this policy, we believe that these features support an enforcement discretion policy for premarket review and most QS requirements in the specific context of LDTs for unmet needs.

This policy is limited to LDTs for unmet needs. FDA considers an LDT to be for an unmet need where there is no available FDA-authorized IVD that meets the patient's needs. This may be because: (1) there is no FDA-authorized IVD for the disease or condition (for example, because it is for a rare disease or condition); (2) there is an FDA-authorized IVD for the disease or condition but it is not indicated for use on the patient, or a unique attribute needs to be added to the LDT to meet the patient's needs; or (3) there is an FDA-authorized IVD but it is not available to the patient. Examples of LDTs for unmet needs are:

• An LDT that is intended for cytogenetic analysis of certain genes and chromosomes associated with rare diseases or conditions, certain metals testing, viral load monitoring for some transplant-associated viruses, or diagnosis of certain mosquito- and tick-borne-diseases, where there is no FDA-authorized IVD for the disease/condition (

rare disease or condition

);

• An LDT to accommodate an alternative specimen type that is infrequently tested when the specimen type required for the FDA-authorized IVD is not and cannot be made available (

variation from the indications for use of an FDA-authorized IVD

);

• An LDT for use on pediatric patients when FDA-authorized IVDs are indicated for use on adults only (

variation from the indications for use of an FDA-authorized IVD

);

• An LDT that generates results in a significantly shorter period (

e.g.,

hours versus days) than an FDA-authorized IVD with the same indication where, due to the circumstances of the patient, the shorter time period to get results is critical for the clinical decision being made (

unique attribute needed to be added to an FDA-authorized IVD

);

• An LDT for the same indication as an FDA-authorized IVD that is offered only in another healthcare system that is not accessible to the patient and the developing laboratory will not make the IVD available outside its system (

FDA-authorized IVD is not available

); and

• An LDT for an emerging pathogen for which there is no FDA-authorized IVD and for which FDA has not identified an emergent situation (

no FDA-authorized IVD

).

In contrast, FDA does not consider an LDT to be for an unmet need when there is an available FDA-authorized IVD that would sufficiently meet the needs of the patient. For example, potential improvements in performance or lower cost in comparison to an FDA-authorized IVD that meets the patient's needs does not fall within this policy.

FDA intends this policy to be targeted. It is not intended to serve as an alternative “pathway” to market for LDTs for unmet needs. FDA intends to provide additional guidance on this enforcement discretion policy, which would be issued in accordance with good guidance practices (see § 10.115).

We note that if there is no longer an unmet need for an LDT because, for example, FDA authorizes an IVD that meets the needs of the patient, then the LDT would no longer fall within this enforcement discretion policy. This will encourage manufacturers, including the manufacturers of LDTs falling within this policy, to seek premarket authorization, without delaying patient access to the LDT. It also will provide patients and providers with greater confidence that once an IVD has been authorized by FDA, all similar devices, regardless of who makes them, should have appropriate assurance of safety and effectiveness because all such devices should comply with premarket review and QS requirements. Moreover, such a limitation helps to ensure that the enforcement discretion policy will ultimately target only those LDTs where there is insufficient financial incentive to seek authorization for the LDTs (in such cases, there is unlikely to ever be an available FDA-authorized IVD).

Notably, this unmet needs LDT policy applies only to LDTs that are validated. We acknowledge that validation may vary depending on many factors, including the accessibility of specimens and the number of affected patients. FDA intends to consider whether issuing additional guidance regarding validation of tests, including those for rare diseases that takes into consideration the challenges in obtaining a robust number of samples for validation, would be helpful.

In developing this policy, FDA took into consideration various factors that mitigate the risk that LDTs offered as described in this policy may not have appropriate assurance of safety and effectiveness. As an initial matter, the phaseout of the general enforcement discretion approach for all other applicable requirements will provide greater assurances regarding these LDTs than the Agency, healthcare providers, and patients currently have. Compliance with registration and listing requirements, for example, will provide FDA and the public with insight into what LDTs for unmet needs are being offered by laboratories integrated within healthcare systems. Moreover, compliance with labeling requirements, including those in § 809.10(b)(12), will help to ensure that healthcare providers and patients have information on the performance of the LDT and thus will help to enable more informed decision making. In addition, FDA generally intends to request that laboratories that offer LDTs as described in this policy submit labeling information to FDA in

connection with the listing of the device as provided in § 807.26(e) (this regulation is discussed above). This labeling will facilitate FDA surveillance for potentially poor performing LDTs that should otherwise be addressed.

Finally, as noted elsewhere in this preamble, regardless of this or any other enforcement discretion policy, FDA retains discretion to pursue enforcement action at any time against violative IVDs when appropriate. We intend to carefully monitor LDTs falling within this policy and intend to take action regarding such LDTs as appropriate taking into account any public health concerns as evaluated on a case-by-case basis.

We considered various alternative policies proposed in comments regarding LDTs for unmet needs and LDTs manufactured by AMC laboratories or laboratories integrated within other healthcare systems, but we believe this policy best serves FDA's public health mission by helping to assure the safety and effectiveness of LDTs while also accounting for patient access. For example, an enforcement discretion policy whereby FDA generally does not enforce premarket review and most QS requirements for

any

LDT manufactured by AMC laboratories and laboratories integrated within other healthcare systems would appear to be overly broad, including because it would encompass LDTs for which there are FDA-authorized alternatives that we know have appropriate assurances of safety and effectiveness. Similarly, an enforcement discretion policy whereby FDA generally does not enforce premarket review and most QS requirements for

all

LDTs for unmet needs would also appear to be overly broad, as there are not the same risk mitigations present for all such LDTs that would help address and avoid the use of problematic LDTs. We also considered several narrower enforcement discretion policies, such as an enforcement discretion policy where a premarket submission would be expected

after

an LDT is offered for use and where the LDT is offered until FDA makes a final decision on the LDT (see,

e.g.,

the 2017 Discussion Paper (Ref. 57)) or a longer phaseout policy for QS requirements. We do not think such policies would make sense here because many laboratories would likely be dissuaded from developing LDTs in this space if compliance with premarket review and QS requirements is routinely expected at any point in time due to the lack of financial incentives and perceived costs associated with premarket review and QS requirements.

Second, FDA intends to exercise enforcement discretion and generally not enforce premarket review and QS requirements (except for requirements under part 820, subpart M (Records))

35

for currently marketed IVDs offered as LDTs that were first marketed prior to the date of issuance of this rule (hereinafter, “currently marketed IVDs offered as LDTs”). FDA intends for this policy to apply to currently marketed IVDs offered as LDTs as long as they are not modified following the issuance of this final rule, or are modified but only in certain limited ways that are described below. This enforcement discretion policy does not apply to any IVDs identified in section V.A.2 as falling outside the scope of the phaseout policy or as discussed in section V.B.

35

As noted in footnote 17, for the categories of IVDs discussed in section V.B.3, FDA generally expects compliance with requirements under part 820, subpart M (Records) but not §§ 820.20, 820.22, 820.40, and 820.50 (which are cross-referenced in subpart M), or comparable provisions of ISO 13485 in accordance with the amendments to part 820 once that rule takes effect in February 2026.

As part of this policy, FDA intends to request submission of the labeling for currently marketed IVDs offered as LDTs under § 807.26(e) and to use this information, along with information obtained through laboratory compliance with other relevant requirements (such as adverse event reporting), to identify and address those currently marketed IVDs offered as LDTs that specifically raise concerns. We recognize that patients, the healthcare community, and the laboratory industry have likely made decisions in reliance on access to, or the continued manufacturing of, many currently marketed IVDs offered as LDTs, and that loss of beneficial currently marketed IVDs offered as LDTs could cause harm and undermine those reliance interests. We believe this policy appropriately balances the various competing interests at issue to best serve public health because it helps facilitate continued access to those IVDs offered as LDTs that are beneficial while incorporating targeted use of available tools to identify and act against currently marketed IVDs offered as LDTs that are problematic. As IVDs evolve, compliance with premarket review and QS requirements will be phased in according to the natural lifecycle of test development and use.

FDA is adopting this policy after a review of the comments, which leads us to conclude that an expectation of compliance with premarket review and QS requirements for currently marketed IVDs offered as LDTs may be more harmful than helpful to the public because, for example, it will prompt many laboratories to stop offering tests even if they are safe and effective. One commenter stated that “[i]f the rule is implemented, it is likely that we would consider no longer offer [

sic

] [IVDs offered as LDTs] due to the administrative and financial burdens of the regulations.” Another commenter stated that “the most prominent reason [the proposed rule should not move forward] is that patient care will suffer as most small laboratories will be forced to close because of increased cost and need to reduce their test menu.” These comments corresponded to data in FDA's Preliminary Regulatory Impact Analysis (PRIA) suggesting a potentially high burden on laboratories associated with compliance for currently marketed IVDs offered as LDTs—a burden that could potentially cause some laboratories (particularly small laboratories) to close (Ref. 60). As reflected in section II.F of the FRIA (Ref. 10), a significant fraction of the estimated overall costs of compliance with applicable requirements under the FD&C Act and FDA's regulations is attributable to premarket review (where applicable) and QS requirements. Specifically, out of the total estimated discounted costs to industry of $1.17 billion, the average estimated costs of compliance with stages 1 and 2 of the phaseout policy (as described in section V.C below) are approximately $9,522 per test ($74,783 per laboratory) and the average estimated costs of compliance with premarket review and QS requirements are approximately $3.02 million per test ($1.26 million per laboratory).

In the NPRM and this preamble, FDA explained that relevant evidence points to a high degree of variability in the performance of IVDs offered as LDTs today, but FDA does not take the view that all laboratory-manufactured IVDs are problematic (see,

e.g.,

88 FR 68006 at 68010-68012 and responses to comments 28, 32-33). We believe that an appreciable proportion of IVDs currently offered as LDTs likely help patients and are important to patient care (see section II.E.1 of the FRIA (Ref. 10)), and as noted above, we understand that patients, the healthcare community, and the laboratory industry have likely made decisions in reliance on access to, or the continued manufacturing of, such IVDs. The loss of such IVDs could cause harm and undermine those reliance interests.

FDA is aware, for instance, that certain patients may have embarked on a course of treatment in reliance on regular testing to help monitor their treatment or condition, and the loss of that testing could pose serious risks and

complications for that patient. For example, consistent access to tests that are already being used to measure plazomicin to aid in the management of patients with complicated urinary tract infection receiving plazomicin therapy and tests to measure levels of immunosuppressants—such as cyclosporine, tacrolimus, everolimus, and sirolimus—in transplant patients are important for treating physicians to make well-informed treatment decisions for those patients. In the context of patients receiving tests that are not well-standardized to monitor their diseases or conditions, consistent access to the same test at the same laboratory over time is also important for treating physicians to make accurate diagnostic and treatment decisions. Examples of such tests include thyroid hormone tests that are used to monitor thyroid disease, adrenal function tests that are used to monitor adrenal disorders, and flow-cytometry-based minimal residual disease tests that are used to monitor patients with cancer that have undergone treatment to determine if they are at risk for relapse.

FDA also recognizes that healthcare professionals may have made significant financial investments in reliance on access to certain tests (

e.g.,

contracts for certain tests that they need for long-term patient monitoring, where such monitoring must continue with the same test because test results are compared over time and results from a different test are not interchangeable), and that the loss of access could harm their practice and, ultimately, the patients they serve. In addition, laboratories may have made financial investments and other decisions based on a past assumption about the presence of the general enforcement discretion approach.

In light of these reliance considerations and, in particular, the risk that laboratories may stop offering safe and effective tests on which patients and the healthcare community currently rely, we do not think it is appropriate to expect compliance with premarket review and most QS requirements for all currently marketed IVDs offered as LDTs. Instead, we have determined it is in the best interest of the public health to expect compliance with premarket review and QS requirements in a more targeted fashion—

i.e.,

for those currently marketed IVDs offered as LDTs that specifically raise concerns. As new IVDs come on the market following issuance of this rule, they will be expected to comply with premarket review and QS requirements—in accordance with the phaseout policy—gradually phasing in those requirements for the overall market. In the meantime, compliance with other applicable requirements will help enable FDA to identify and address safety and effectiveness problems that may arise.

In deciding on this policy, FDA considered alternatives to address the concerns identified above, including the risk of market exit, such as: (1) extending the phaseout timeline to give more time for currently marketed IVDs offered as LDTs to come into compliance with premarket review and QS requirements and (2) expecting compliance with premarket review and QS requirements only for high-risk currently marketed IVDs offered as LDTs. However, based on FDA's economic projections, neither of these alternatives resolves the concern about market exit resulting in loss of access to beneficial IVDs on which patients and others currently rely because neither substantially changes the economic burden on laboratories. For example, under Alternative 3 in section II.J of the PRIA, FDA evaluated the reduction in burden of an extended phaseout policy, and based on the calculations there, we doubt that the reduction would be sufficient to prevent the outcomes described above (see Ref. 60). In addition, the PRIA shows that the greatest costs in the phaseout policy are those associated with high-risk IVDs, so a policy that involves compliance for currently marketed high-risk IVDs offered as LDTs also would not resolve the concern about market exit. Given this information, and given the information we received in comments, FDA has concluded that the best course is to adopt the policy for currently marketed IVDs offered as LDTs outlined above. (This policy is keyed to the date of this final rule, rather than the proposed rule, because patients and the healthcare community may have begun relying on IVDs during the period between publication of the proposed and final rule.)

Based on FDA's understanding of the current IVD industry, we expect IVDs offered as LDTs to continue to advance to meet new patient needs, accommodate new technologies, and incorporate the latest scientific findings. Under this policy for currently marketed IVDs offered as LDTs, when such IVDs are modified in certain significant ways that would, under FDA requirements, generally prompt the need for premarket review relative to the original currently marketed IVD, FDA expects laboratories to comply with premarket review and QS requirements for that modified IVD. This policy is intended to preserve access to beneficial IVDs on which patients and the healthcare community currently rely, including versions of that IVD with minor changes. However, we expect compliance with premarket review and QS requirements once the IVD is changed in certain, more significant ways that could affect its basic safety and effectiveness profile. In particular, under this policy, FDA generally expects compliance with premarket review and QS requirements for currently marketed IVDs offered as LDTs when a laboratory's modifications (individually or in aggregate):

• change the indications for use of the IVD;

• alter the operating principle of the IVD (

e.g.,

changes in critical reaction components);

• include significantly different technology in the IVD (

e.g.,

addition of artificial intelligence or machine learning to the test algorithm, a change from targeted sequencing to whole genome sequencing, a change from immunoassay to mass spectrometry, or a change from manual to automated procedures); or

• adversely change the performance or safety specifications of the IVD.

36

36

Under FDA regulations, the listed modifications to an IVD would generally require a new submission, such as a new 510(k), PMA, BLA, or De Novo, or certain types of PMA or BLA supplements.

See, e.g.,

21 CFR 601.2, 601.12, 807.81(a)(3), 814.39, and 860.200; see also “Deciding When to Submit a 510(k) for a Change to an Existing Device” (Ref. 61).

FDA believes this approach appropriately limits the scope of this policy and reduces the risk for patients.

As noted above, FDA also intends to take targeted steps to address currently marketed IVDs offered as LDTs that are problematic. In particular, we intend to use available tools to identify and act against currently marketed IVDs offered as LDTs that specifically raise concerns, such as IVDs that are potentially inaccurate or poorly validated. In this way, FDA can work to assure the safety and effectiveness of currently marketed IVDs offered as LDTs without creating the risk of widespread market exit. FDA has a range of tools to assist in this effort.

First, FDA intends to request that laboratories offering currently marketed IVDs offered as LDTs submit labeling to FDA as provided in § 807.26(e). Labeling includes IVD performance information and a summary of supporting validation, as applicable. This information will help FDA more closely monitor currently marketed IVDs offered as LDTs and identify those that may lack analytical validity, clinical validity, or safety. As part of its review of labeling, FDA also intends to

look closely at claims of superior performance and whether those claims are adequately substantiated.

37

Such claims are of particular public health concern because, in FDA's experience, they have led to escalating claims from competitors that can ultimately mislead the public. FDA generally intends to take action where the labeling of a currently marketed IVD offered as an LDT is false or misleading, and/or the IVD offered as an LDT lacks the appropriate assurance of safety and effectiveness for its intended uses as a result of any such claims that are not adequately substantiated.

37

See, e.g.,

FDA, Final Guidance for Industry: Medical Product Communications That Are Consistent With the FDA-Required Labeling—Questions and Answers at 18 (June 2018) (“[P]romotional material is misleading” when “it makes a claim of superior effectiveness for Drug A versus Drug B based on a study that was not designed to establish superiority of Drug A to Drug B.”).

See

Ref. 62.

Second, FDA intends to enforce records requirements in part 820, subpart M, for manufacturing activities related to a currently marketed IVD offered as an LDT that occur after the date of issuance of this final rule. Compliance with these requirements will facilitate FDA's review of these IVDs during inspections, enabling FDA to understand the validation bases and processes underlying these IVDs, and will support appropriate adverse event reporting (MDRs).

Third, under the policy, FDA expects laboratories to comply with applicable requirements other than premarket review and most QS requirements, including MDR requirements, corrections and removals reporting requirements, registration and listing requirements, and labeling requirements. Compliance with these requirements will provide FDA with additional important information regarding currently marketed IVDs offered as LDTs, such as information enabling FDA to track adverse-event trends.

Finally, based on our experience with other devices, we anticipate that laboratory manufacturers will alert us to potential problems with their competitors' IVDs once IVD performance information is transparent, which will help direct FDA's attention to problematic tests.

FDA emphasizes that these tools are not a substitute for premarket review or full QS compliance. FDA continues to believe that premarket review and full QS compliance are important tools to help assure the safety and effectiveness of IVDs going forward. However, there are sufficient countervailing reasons to take a more targeted approach for currently marketed IVDs offered as LDTs, including the risk of market exit and the potentially significant reliance on currently marketed IVDs offered as LDTs. Thus, FDA has determined that the enforcement discretion policy outlined above best serves public health.

The third category of tests for which FDA intends to exercise enforcement discretion and generally not enforce premarket review and QS requirements (except for requirements under part 820, subpart M (Records))

38

is non-molecular antisera LDTs

39

for rare RBC antigens when such tests are manufactured and performed by blood establishments, including transfusion services and immunohematology laboratories

40

and when there is no alternative IVD available to meet the patient's need for a compatible blood transfusion. This policy does not apply to molecular tests used for genotyping RBC antigens. This policy also does not apply to any IVDs identified in section V.A.2 as falling outside the scope of the phaseout policy or as discussed in section V.B.

38

As noted in footnote 17, for the categories of IVDs discussed in section V.B.3, FDA generally expects compliance with requirements under part 820, subpart M (Records) but not §§ 820.20, 820.22, 820.40, and 820.50 (which are cross-referenced in subpart M), or comparable provisions of ISO 13485 in accordance with the amendments to part 820 once that rule takes effect in February 2026.

39

Consistent with what FDA has generally considered to be an LDT (as discussed elsewhere in this preamble), this enforcement discretion policy applies only to tests that are designed, manufactured, and used within a single CLIA-certified laboratory that meets the requirements under CLIA for high complexity testing.

40

In our experience, establishments that perform compatibility tests for blood transfusion include establishments, such as reference laboratories, that are not integrated within a healthcare system. Therefore, the non-molecular antisera LDTs at issue may not fall within the policy described above for LDTs manufactured and performed by a laboratory integrated within a healthcare system to meet an unmet need of patients receiving care within the same healthcare system.

Some individuals develop antibodies to certain antigens that they lack on their own RBCs following exposure to foreign RBC antigens through blood transfusion or pregnancy. These may be clinically significant, causing a hemolytic transfusion reaction if the patient receives a transfusion of RBCs that have the corresponding antigen(s). As of July 2023, there are currently 45 recognized blood group systems containing 360 RBC antigens (Ref. 63). FDA understands that there are occasions where licensed antisera IVDs are not available for rare RBC antigens but testing for such rare antigens is necessary to help ensure that patients receive a compatible blood transfusion

41

and avoid potentially life-threatening reactions. Although FDA has also approved molecular tests for use in genotyping RBC antigens, there may not be an available, approved molecular test to use as an alternative for all rare antigens.

41

Such tests are not subject to the requirements in § 640.5. As noted elsewhere in this document, FDA's general enforcement discretion approach for LDTs has not applied to tests for determination of blood group and Rh factors that are subject to § 640.5.

FDA is adopting this policy after consideration of comments that requested that FDA continue to exercise enforcement discretion with respect to antisera LDTs for rare RBC antigens and/or molecular tests for genotyping rare RBC antigens. This included comments pointing to FDA's existing 2018 final guidance (Ref. 64), which, among other things, recognized that blood establishments sometimes use unlicensed antisera tests or unapproved molecular tests for RBC antigen typing in circumstances where a licensed reagent for a rare antigen is not available.

The non-molecular antisera LDTs within the scope of this policy share certain characteristics with “1976-Type LDTs,” as they use manual techniques performed by laboratory personnel with specialized expertise. For such LDTs, in instances where there is no available alternative to ensure that a patient receives a compatible transfusion, FDA has determined it is in the best interest of public health to adopt this enforcement discretion policy. However, this policy does not apply to molecular tests for genotyping RBC antigens. Compared to serologic tests, molecular RBC typing is a relatively new and complex technique for detection of RBC antigens. Some limitations of molecular RBC typing tests include that the genotype does not always correlate with the phenotype due to samples with rare null phenotypes, and the assay may not be designed to detect all rare or new variants of an antigen. As such, FDA has greater concern regarding risk of error with molecular tests for genotyping RBC antigens that do not comply with applicable FDA requirements.

For LDTs offered as described in this policy, FDA expects the LDT to be validated. As discussed previously, we acknowledge that such expectations may vary depending on many factors, including the accessibility of specimens and the number of affected patients.

In addition, this enforcement policy applies only to premarket review and QS requirements (except for

requirements under part 820, subpart M (Records)). FDA expects compliance with records requirements in part 820, subpart M, for non-molecular antisera LDTs that fall within this policy. Compliance with these requirements will facilitate FDA's review of these LDTs during inspections and will support appropriate adverse event reporting. The phaseout of the general enforcement discretion approach for other applicable requirements will provide greater assurances regarding tests that fall within this policy than the Agency, healthcare providers, and patients currently have.

Finally, as noted elsewhere in this preamble, regardless of this or any other enforcement discretion policy, FDA retains discretion to pursue enforcement action at any time against violative IVDs. We intend to carefully monitor LDTs falling within this policy and intend to take action regarding such LDTs as appropriate, taking into account any public health concerns as evaluated on a case-by-case basis.

C. Stages

As previously discussed, FDA has determined to gradually phase out its current general enforcement discretion approach for LDTs so that IVDs manufactured by a laboratory will generally fall under the same enforcement approach as other IVDs. In particular, FDA has structured the phaseout policy to contain five key stages:

•

Stage 1:

beginning 1 year after the publication date of this final rule, FDA will expect compliance with MDR requirements, correction and removal reporting requirements, and QS requirements under § 820.198 (complaint files).

•

Stage 2:

beginning 2 years after the publication date of this final rule, FDA will expect compliance with requirements not covered during other stages of the phaseout policy, including registration and listing requirements, labeling requirements, and investigational use requirements.

•

Stage 3:

beginning 3 years after the publication date of this final rule, FDA will expect compliance with QS requirements under part 820 (other than requirements under § 820.198 (complaint files), which are already addressed in stage 1).

•

Stage 4:

beginning 3

1/2

years after the publication date of this final rule, FDA will expect compliance with premarket review requirements for high-risk IVDs offered as LDTs, unless a premarket submission has been received by the beginning of this stage in which case FDA intends to continue to exercise enforcement discretion for the pendency of its review.

•

Stage 5:

beginning 4 years after the publication date of this final rule, FDA will expect compliance with premarket review requirements for moderate-risk and low-risk IVDs offered as LDTs (that require premarket submissions), unless a premarket submission has been received by the beginning of this stage in which case FDA intends to continue to exercise enforcement discretion for the pendency of its review.

These stages, along with certain narrower enforcement discretion policies specific to certain stages, are discussed in further detail below.

We note that FDA generally does not intend to enforce requirements to include certain information (

e.g.,

registration numbers, premarket submission numbers) in reports or other submissions to the Agency until the information is addressed in a later stage of the phaseout policy.

We received several comments on the structure, sequencing, and timing of the proposed phaseout policy described in the NPRM (see section VI.F.6 of this preamble). Some indicated that the proposed timing for all phases was appropriate while others recommended it be shortened or lengthened. Some also proposed different approaches for organizing or implementing the phaseout.

FDA carefully considered these comments, and also considered the impact of other policies included in the final phaseout policy on the considerations noted in these comments. For the reasons discussed below and in section VI.F.6, FDA has determined that it should retain the general structure, sequencing, and timelines proposed in the NPRM (88 FR 68006 at 68021) for the phaseout policy in this final rule.

FDA encourages laboratory manufacturers to begin early and work toward compliance with requirements sooner than the end of the timeframes specified for each stage of the phaseout policy, as described below. FDA also intends to consider providing more targeted guidance and/or making additional resources available on specific topics, such as compliance with applicable labeling requirements, over the course of the phaseout period, as discussed in section VI.P.

1. Stage 1: Beginning 1 Year After the Publication Date of This Final Rule, FDA Will Expect Compliance With MDR Requirements, Correction and Removal Reporting Requirements, and QS Requirements Under § 820.198 (Complaint Files)

As detailed elsewhere in this preamble, FDA is concerned that some IVDs offered as LDTs may be posing risks to patients; therefore, FDA seeks to obtain information about potentially harmful IVDs offered as LDTs as soon

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